SMART MODE:

NORMAL GENOMIC

• Rosengren KJ, Daly NL, Scanlon MJ, Craik DJ
• Solution structure of BSTI: a new trypsin inhibitor from skin secretions of Bombina bombina.
• Biochemistry. 2001; 40: 4601-9
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• The three-dimensional solution structure of BSTI, a trypsin inhibitor from the European frog Bombina bombina, has been solved using (1)H NMR spectroscopy. The 60 amino acid protein contains five disulfide bonds, which were unambiguously determined to be Cys (4--38), Cys (13--34), Cys (17--30), Cys (21--60), and Cys (40--54) by experimental restraints and subsequent structure calculations. The main elements of secondary structure are four beta-strands, arranged as two small antiparallel beta-sheets. The overall fold of BSTI is disk shaped and is characterized by the lack of a hydrophobic core. The presumed active site is located on a loop comprising residues 21--34, which is a relatively disordered region similar to that seen in many other protease inhibitors. However, the overall fold is different to other known protease inhibitors with the exception of a small family of inhibitors isolated from nematodes of the family Ascaris and recently also from the haemolymph of Apis mellifera. BSTI may thus be classified as a new member of this recently discovered family of protease inhibitors.

• Solans A, Estivill X, de La Luna S
• A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein beta-secretase.
• Cytogenet Cell Genet. 2000; 89: 177-84
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• Down syndrome individuals develop abnormalities of most organs, including all the pathological and neurochemical features of Alzheimer's disease, by the early age of 30 yr. Here, we report the isolation and characterization of BACE2, a gene mapping on human chromosome 21q22.3, which is highly similar to a transmembrane aspartyl protease, BACE (for beta-site APP-cleaving enzyme), which is able to catalyze the beta-secretase cleavage of Alzheimer's amyloid precursor protein (APP). BACE2 is expressed in a wide variety of organs and tissues, with several transcripts due to alternative splicing and the use of two polyadenylation signals. The BACE2 gene product is a 518 amino acid protein with the signature of an aspartic protease, a 20-residue signal peptide, and two putative N-glycosylation sites. In addition, and similarly to BACE, BACE2 differs from the other members of the human aspartic protease family in the number and distribution of putative disulfide bonds and in the presence of an extended C-terminal region which contains a predicted transmembrane segment. BACE2 could be involved in the Alzheimer-like neuropathology of Down syndrome, as well as in Alzheimer's disease linked to chromosome 21 but not showing mutations in APP.

• Bayer TA, Cappai R, Masters CL, Beyreuther K, Multhaup G
• It all sticks together--the APP-related family of proteins and Alzheimer's disease.
• Mol Psychiatry. 1999; 4: 524-8
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• In the present review, we shall discuss the pros and cons of a possible functional relationship and contribution of the APP family members (APP, APLP1 and APLP2) to the development of Alzheimer's disease: (1) APP, APLP1 and APLP2 are highly homologous proteins with similar protein domain organization. (2) All APP family proteins have been found to be aggregated in typical Alzheimer's disease lesions. (3) Several other proteins have been implied to provide a functional link among the APP-related proteins. In normal adult brain APP, APLP1 and APLP2 are involved in synaptic processes important for memory function. We hypothesize that the functional loss of members of the APP family contributes to the gradual cognitive decline in Alzheimer's disease patients.

• Vogel G
• Possible new cause of Alzheimer's disease found.
• Science. 1998; 279: 174-174

• Little SP et al.
• Zyme, a novel and potentially amyloidogenic enzyme cDNA isolated from Alzheimer's disease brain.
• J Biol Chem. 1997; 272: 25135-42
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• The deposition of the beta amyloid peptide in neuritic plaques and cerebral blood vessels is a hallmark of Alzheimer's disease (AD) pathology. The major component of the amyloid deposit is a 4.2-kDa polypeptide termed amyloid beta-protein of 39-43 residues, which is derived from processing of a larger amyloid precursor protein (APP). It is hypothesized that a chymotrypsin-like enzyme is involved in the processing of APP. We have discovered a new serine protease from the AD brain by polymerase chain reaction amplification of DNA sequences representing active site homologous regions of chymotrypsin-like enzymes. A cDNA clone was identified as one out of one million that encodes Zyme, a serine protease. Messenger RNA encoding Zyme can be detected in some mammalian species but not in mice, rats, or hamster. Zyme is expressed predominantly in brain, kidney, and salivary gland. Zyme mRNA cannot be detected in fetal brain but is seen in adult brain. The Zyme gene maps to chromosome 19q13.3, a region which shows genetic linkage with late onset familial Alzheimer's disease. When Zyme cDNA is co-expressed with the APP cDNA in 293 (human embryonic kidney) cells, amyloidogenic fragments are detected using C-terminal antibody to APP. These co-transfected cells release an abundance of truncated amyloid beta-protein peptide and shows a reduction of residues 17-42 of Abeta (P3) peptide. Zyme is immunolocalized to perivascular cells in monkey cortex and the AD brain. In addition, Zyme is localized to microglial cells in our AD brain sample. The amyloidogenic potential and localization in brain may indicate a role for this protease in amyloid precursor processing and AD.

• Hensley K et al.
• Reactive oxygen species as causal agents in the neurotoxicity of the Alzheimer's disease-associated amyloid beta peptide.
• Ann N Y Acad Sci. 1996; 786: 120-34

• Koch D, Abraham CR
• [Alzheimer's disease and the significance of amyloid-beta protein in its pathogenesis]
• Harefuah. 1995; 128: 156-9

• Slunt HH, Thinakaran G, Von Koch C, Lo AC, Tanzi RE, Sisodia SS
• Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP).
• J Biol Chem. 1994; 269: 2637-44
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• Alzheimer's disease is characterized by the presence of senile plaques comprised primarily of deposits of the beta-amyloid protein (A beta) derived from larger amyloid precursor proteins (APP). We have identified a cDNA that encodes a 751-amino acid APP-like protein (designated APLP2) from the mouse that, with exception of the A beta region, is highly homologous to APP. In situ hybridization and quantitative polymerase chain reaction reveal that APLP2 and APP mRNA are expressed in similar, if not identical, neuronal populations and at similar levels. APLP2 appears to mature through the same unusual secretory/cleavage pathway as APP. Furthermore, widely utilized antibodies generated against non-overlapping epitopes of APP do not discriminate between APP and APLP2. Although APLP2 cannot give rise to A beta, its near identity to APP outside the A beta domain confounds the interpretation of previous immunocytochemical and biochemical characterizations of APP biosynthesis and metabolism.

• Yoshikawa K
• [Molecular neurobiology of Alzheimer amyloid protein precursor]
• Seikagaku. 1993; 65: 1149-59

• Liepnieks JJ, Ghetti B, Farlow M, Roses AD, Benson MD
• Characterization of amyloid fibril beta-peptide in familial Alzheimer's disease with APP717 mutations.
• Biochem Biophys Res Commun. 1993; 197: 386-92
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• Amyloid fibrils were isolated from the brain tissue of two individuals who died with familial Alzheimer's disease, one with the phenylalanine 717 mutation in amyloid precursor protein (APP) and one with the isoleucine 717 APP mutation. After solubilization in guanidine hydrochloride and fractionation by sieve chromatography, low molecular weight fractions were treated with cyanogen bromide to generate the beta-peptide fragment starting after the methionine at position 35. Amino acid sequence analysis of all resultant peptides identified the peptide Val-Gly-Gly-Val-Val-Ile-Ala which represents residues 36-42 of the beta-amyloid peptide. No sequence beyond position 42 was found. These findings show that the amino acid substitution at position 717 is not incorporated into the amyloid deposits and suggests that the mutation may have metabolic affects which determine pathogenesis.

• Ueda K et al.
• Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease.
• Proc Natl Acad Sci U S A. 1993; 90: 11282-6
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• A neuropathological hallmark of Alzheimer disease (AD) is a widespread amyloid deposition. We analyzed the entire amino acid sequences in an amyloid preparation and found, in addition to the major beta/A4-protein (A beta) fragment, two unknown peptides. We raised antibodies against synthetic peptides using subsequences of these peptides. These antibodies immunostained amyloid in neuritic and diffuse plaques as well as vascular amyloid. Electron microscopic analysis demonstrated that the immunostaining was localized on amyloid fibrils. We have isolated an apparently full-length cDNA encoding a 140-amino-acid protein within which two previously unreported amyloid sequences are encoded in tandem in the most hydrophobic domain. We tentatively named this 35-amino acid peptide NAC (non-A beta component of AD amyloid) and its precursor NACP. NAC is the second component, after A beta, identified chemically in the purified AD amyloid preparation. Secondary structure predictions indicate that the NAC peptide sequence has a strong tendency to form beta-structures consistent with its association with amyloid. NACP is detected as a M(r) 19,000 protein in the cytosolic fraction of brain homogenates and comigrates on immunoblots with NACP synthesized in Escherichia coli from NACP cDNA. NACP mRNA is expressed principally in brain but is also expressed in low concentrations in all tissues examined except in liver, suggesting its ubiquitous and brain-specific functions. The availability of the cDNA encoding full-length NACP should help to elucidate the mechanisms of amyloidosis in AD.

• Denman RB, Rosenzcwaig R, Miller DL
• A system for studying the effect(s) of familial Alzheimer disease mutations on the processing of the beta-amyloid peptide precursor.
• Biochem Biophys Res Commun. 1993; 192: 96-103
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• Three different point mutations have been observed in some familial Alzheimer's disease pedigrees at a unique valine, Val717, near the carboxyl end of the beta Amyloid Peptide Precursor (beta APP). The effects of these mutations on the processing and cellular functions of beta APP can best be determined in the absence of the normal form(s) of the protein. We have used targeted mRNA degradation by a trans-acting hammerhead ribozyme to cleave and inactivate beta APP expression in vitro. The consensus ribozyme cleavage site, 5'GUC decreases X3, matches the Val717 nucleotide sequence in beta APP mRNA. Introduction of FAD point mutations which change Val717 decrease the rate of ribozyme cleavage by more than three orders of magnitude. Thus, ribozyme targeting of this site should allow the study of protein processing in vivo. Furthermore, a ribozyme targeted to mutant beta APP mRNA (Val717-->Ile) cleaved the mutant sequence 300-fold faster than the normal sequence. This suggests that ribozymes might lower mutant beta APP mRNA levels in FAD cells.

• Wasco W et al.
• Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid beta protein precursor.
• Nat Genet. 1993; 5: 95-100
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• Familial Alzheimer's disease (FAD) is a genetically heterogeneous disorder that includes a rare early-onset form linked to mutations in the amyloid b protein precursor (APP) gene. Clues to the function of APP derive from the recent finding that it is a member of a highly conserved protein family that includes the mammalian amyloid precursor-like protein (APLP1) gene which maps to the same general region of human chromosome 19 linked to late-onset FAD. Here we report the isolation of the human APLP2 gene. We show that APLP2 is a close relative of APP and exhibits a very similar pattern of expression in the brain and throughout the body. Like APP, APLP2 contains a cytoplasmic domain predicted to couple with the GTP-binding protein G(o) indicating that it may be an additional cell surface activator of this G protein.

• Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, Solomon F
• Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor.
• Proc Natl Acad Sci U S A. 1992; 89: 10758-62
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• We have isolated a cDNA from a mouse brain library that encodes a protein whose predicted amino acid sequence is 42% identical and 64% similar to that of the amyloid beta protein precursor (APP). This 653-amino acid protein, which we have termed the amyloid precursor-like protein (APLP), appears to be similar to APP in overall structure as well as amino acid sequence. The amino acid homologies are concentrated within three distinct regions of the two proteins where the identities are 47%, 54%, and 56%. The APLP cDNA hybridizes to two messages of approximately 2.4 and 1.6 kilobases that are present in mouse brain and neuroblastoma cells. Polyclonal antibodies raised against a peptide derived from the C terminus of APLP stain the cytoplasm in a pattern reminiscent of Golgi staining. In addition to APP, APLP also displays significant homology to the Drosophila APP-like protein APPL and a rat testes APP-like protein. These data indicate that the APP gene is a member of a strongly conserved gene family. Studies aimed at determining the functions of the proteins encoded by this gene family should provide valuable clues to their potential role in Alzheimer disease neuropathology.

• Hynes TR, Randal M, Kennedy LA, Eigenbrot C, Kossiakoff AA
• X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid beta-protein precursor.
• Biochemistry. 1990; 29: 10018-22
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• Alzheimer's amyloid beta-protein precursor contains a Kunitz protease inhibitor domain (APPI) potentially involved in proteolytic events leading to cerebral amyloid deposition. To facilitate the identification of the physiological target of the inhibitor, the crystal structure of APPI has been determined and refined to 1.5-A resolution. Sequences in the inhibitor-protease interface of the correct protease target will reflect the molecular details of the APPI structure. While the overall tertiary fold of APPI is very similar to that of the Kunitz inhibitor BPTI, a significant rearrangement occurs in the backbone conformation of one of the two protease binding loops. A number of Kunitz inhibitors have similar loop sequences, indicating the structural alteration is conserved and potentially an important determinant of inhibitor specificity. In a separate region of the protease binding loops, APPI side chains Met-17 and Phe-34 create an exposed hydrophobic surface in place of Arg-17 and Val-34 in BPTI. The restriction this change places on protease target sequences is seen when the structure of APPI is superimposed on BPTI complexed to serine proteases, where the hydrophobic surface of APPI faces a complementary group of nonpolar side chains on kallikrein A versus polar side chains on trypsin.

• Katunuma N
• New biological functions of intracellular proteases and their endogenous inhibitors as bioreactants.
• Adv Enzyme Regul. 1990; 30: 377-92
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• Many unexpected biological functions as bioreactants of the intracellular proteases and their endogenous inhibitors have been found recently. Chymase and tryptase in histamine granules of mast cells and basophile cells play an important role in the process of IgE-mediated degranulation and in the formation of an allergic inflammation profile. Furthermore, the relationship between membrane proteases and their endogenous inhibitor has been taken up as a key and key-hole relation which plays an important role for special recognition apparatus of biological information like the relation of peptide hormones (growth factors) and their specific receptors. Amino acid sequences of the active site of trypstatin are homologous with the neutralizing epitope beta of gp120 of AIDS virus (HIV-1). The trypstatin and anti-tryptase M antibody inhibited syncytium formation in HIV infected Molt 4, clone 8 cells. Therefore, the relationship between tryptase M with trypstatin and the recognition site of epitope beta of HIV-1 with the receptor of helper T-cells are the common keys. The precursor of Alzheimer's deposition protein contains a Kunitz-type trypsin inhibitor domain. The A4-precursor proteins are located in axons of pyramidal neurons in brain and secretory granules of chromaffin cells in adrenal medulla. Those may be secreted into the extracellular milieu. We propose that the A4 inhibitor inhibits a special type of tryptase in the brain and disturbs the complete degradation of secreted A4-precursor protein causing amyloid deposition in alzheimer disease by abnormal proteolysis. Human c-Ha-ras p21 shows 58% homology with cystatin beta, an endogenous inhibitor of cathepsin. Actually, p21 inhibits cathepsin L specifically, but not cathepsin H, papain and cathepsin B. However, the metabolic significance of this inhibitory activity is still unknown.

• Higgins GA, Oyler GA, Neve RL, Chen KS, Gage FH
• Altered levels of amyloid protein precursor transcripts in the basal forebrain of behaviorally impaired aged rats.
• Proc Natl Acad Sci U S A. 1990; 87: 3032-6
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• The beta/A4 protein is a constituent of plaque and vascular amyloid deposits in Alzheimer disease. Previous studies have shown increased levels of amyloid protein precursor (APP) mRNA in basal forebrain neurons in the disease. Morphological and neurochemical changes occur within the forebrain in Alzheimer disease and are also correlated with behavioral impairments in aged rats. Recent studies suggest that decreased nerve growth factor responsiveness of basal forebrain neurons is a feature of normal aging and of Alzheimer disease. We have used in situ hybridization to show that the abundance of specific forms of APP mRNA, which contain an inserted Kunitz-type serine protease inhibitor motif (APP-751, APP-770, and APP-related 563), are increased relative to the noninserted form (APP-695) of APP mRNA in the basal forebrain of aged rats. This increase appears to be specific to animals who exhibit spatial memory deficits but not aged rats without behavioral impairments.

• Yan YC, Bai Y, Wang LF, Miao SY, Koide SS
• Characterization of cDNA encoding a human sperm membrane protein related to A4 amyloid protein.
• Proc Natl Acad Sci U S A. 1990; 87: 2405-8
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• A rat testis lambda gt11 cDNA library was screened with a monoclonal antibody raised against a human sperm membrane protein designated YWK-II. A clone was found with a cDNA insert composed of 1837 base pairs that contained an open reading frame coding for 191 amino acid residues. The deduced polypeptide contained a segment with high homology to the transmembrane-cytoplasmic domains of the A4 amyloid protein found in brain plaques of Alzheimer disease patients. A sequence of basic amino acid residues, Arg-Lys-Arg, was found instead of Lys-Lys-Lys at the probable membrane-cytoplasmic junction that may be a unique property of sperm membrane proteins.

• Neve RL, Rogers J, Higgins GA
• The Alzheimer amyloid precursor-related transcript lacking the beta/A4 sequence is specifically increased in Alzheimer's disease brain.
• Neuron. 1990; 5: 329-38
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• The deposition of cerebrovascular and plaque amyloid in the CNS is a primary feature of Alzheimer's disease and aged Down's syndrome pathology. The localization of the Alzheimer amyloid protein precursor (APP) gene on chromosome 21, along with its overexpression in Down's syndrome brain compared with normal brain, suggests that alterations in APP gene expression may play a role in the development of the neuropathology common to the two diseases. In the present report, we demonstrate that a specific spliced form of mRNA that is transcribed from the APP gene and that lacks the beta/A4 sequence is elevated in the nucleus basalis, occipitotemporal cortex, and parahippocampal gyrus in Alzheimer's disease brain relative to controls. These results are based on combined data from RNA slot blot analysis, in situ hybridization, and polymerase chain reaction quantification of specific mRNAs taken directly from tissue sections.

• Kang J, Muller-Hill B
• Differential splicing of Alzheimer's disease amyloid A4 precursor RNA in rat tissues: PreA4(695) mRNA is predominantly produced in rat and human brain.
• Biochem Biophys Res Commun. 1990; 166: 1192-200
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• Alzheimer's disease is characterized by filamentous depositions of amyloid A4 protein in the brain. The first precursor of A4 protein that has been described consists of 695 amino acids (PreA4(695)). Until now, three types of amyloid precursor mRNAs (PreA4(770), PreA4(751) and PreA4(695)), produced by alternative splicing, have been detected. We analysed the differential expression of these mRNAs in various rat tissues by PCR and show that (1) there exists a fourth type of mRNA, PreA4(714); (2) in all tissues except the brain the PreA4(695) mRNA is less abundant than the other types of mRNAs; in the brain, however, the PreA4(695) mRNA predominates by far. The same observations hold true for human tissues. The possible function of this differential splicing is discussed.

• Ohyagi Y, Takahashi K, Kamegai M, Tabira T
• Developmental and differential expression of beta amyloid protein precursor mRNAs in mouse brain.
• Biochem Biophys Res Commun. 1990; 167: 54-60
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• S1 nuclease analysis was used to determine the levels and patterns of three beta amyloid protein precursor (BPP) mRNAs in mouse developmental brain and in primary neuronal and glial cultures. BPP695 mRNA lacking the Kunitz proteinase inhibitor (KPI) domain was detected exclusively in neuronal cultures and increased considerably in late embryonic and early postnatal periods. On the other hand, BPP751 and 770 mRNAs with KPI domain were detected predominantly in astrocyte- and microglia-enriched cultures and increased slightly only in embryonic stages. These results suggest that the product of each BPP mRNA may play a different role in the brain.

• Quon D, Catalano R, Cordell B
• Fibroblast growth factor induces beta-amyloid precursor mRNA in glial but not neuronal cultured cells.
• Biochem Biophys Res Commun. 1990; 167: 96-102
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• Treatment of PC12 and C6 cell cultures with recombinant basic fibroblast growth factor results in approximately a five to ten-fold stimulation of beta-amyloid precursor mRNA in the C6 astrocytoma cell line but only a slight induction of precursor mRNA in the PC-12 neuronal cell line. Stimulation of expression occurred at a hormone concentration of approximately 0.5 to 1 nM and was seen after 2 days. These results suggest that basic fibroblast growth factor may contribute to amyloidosis of Alzheimer's disease.

• Skern T, Zorn M, Blaas D, Kuechler E, Sommergruber W
• Protease or protease inhibitor?
• Nature. 1990; 344: 26-26

• Golde TE, Estus S, Usiak M, Younkin LH, Younkin SG
• Expression of beta amyloid protein precursor mRNAs: recognition of a novel alternatively spliced form and quantitation in Alzheimer's disease using PCR.
• Neuron. 1990; 4: 253-67
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• We have analyzed alternatively spliced beta amyloid protein precursor (beta APP) mRNAs by using the polymerase chain reaction to amplify beta APP cDNAs produced by reverse transcription. With this approach the three previously characterized beta APP mRNAs (beta APP695, beta APP751, and beta APP770) are readily detected and compared in RNA samples extracted from specimens as small as a single cryostat section. We show that the results obtained with this method are not affected by partial RNA degradation and use it to identify a novel alternatively spliced beta APP714 mRNA that is present at low abundance in each of the many human brain regions, peripheral tissues, and cell lines that we have examined; demonstrate that nonneuronal cells in the adult human brain and meninges produce appreciable beta APP695, beta APP751, and beta APP770 mRNA; and identify changes in beta APP gene expression in the AD brain and meninges that may contribute to amyloid deposition.

• Shelton ER et al.
• Characterization of beta-amyloid precursor proteins with or without the protease-inhibitor domain using anti-peptide antibodies.
• J Neurochem. 1990; 55: 60-9
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• Alternative splicing of the transcript encoding the beta-amyloid precursor protein (BAPP) of Alzheimer's disease produces multiple mRNA species. Translation of these mRNAs predicts protein products of 770, 751, and 695 amino acids. The difference arises from the inclusion in BAPP-770/751 of a 56-residue insert region which is homologous to Kunitz-type protease inhibitors. We have prepared and affinity-purified anti-peptide antibodies that react specifically with either BAPP-770/751 (insert-specific) or BAPP-695 (junction-specific). A detectable level of the mRNA corresponding to the BAPP-770/751 protein was found in all cell lines tested. Immunoprecipitation of 35S-labeled proteins from these cell lines showed them to contain one or two Mr 105,000 bands reactive with the insert-specific serum, i-291. In contrast, only cos-7 cells and the human neuroblastoma cell line, IMR-32, contained mRNA species that encode the BAPP-695 protein, as shown by Northern analysis with a junction-spanning oligonucleotide probe. A band of Mr 95,000 was immunoprecipitated specifically from these two cell lines using the junction-specific serum, J-284. Indirect immunofluorescence labeling of cells corroborated these findings. All cells reacted with the insert-specific antibodies, i-291 and i-324. Only cos-7 and IMR-32 cells reacted with the junction-specific antibody, J-284. These results demonstrate the usefulness of anti-peptide antibodies for the differential detection of the BAPP-695 and BAPP-770/751 proteins.

• Kitaguchi N et al.
• Enzyme specificity of proteinase inhibitor region in amyloid precursor protein of Alzheimer's disease: different properties compared with protease nexin I.
• Biochim Biophys Acta. 1990; 1038: 105-13
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• Senile plaques, often surrounded by abnormally grown neurites, are characteristic of Alzheimer's diseased brain. The core of the plaque is mainly composed of amyloid beta protein (beta-AP), two of whose three precursors (APP) have serine proteinase inhibitor regions (APPI). APPI derivatives containing 60, 72 or 88 amino-acid fragments (APPI-60, APPI-72 and APPI-88, respectively) of the longest APP were produced in COS-1 cell culture medium, with the APPI cDNA ligated to the signal sequence of tissue plasminogen activator. The secreted APPIs were purified by sequential acetone precipitation followed by affinity chromatography using immobilized trypsin. These three APPIs and O-glycosylation-site-mutated APPI showed similar inhibitory activity against trypsin, chymotrypsin and plasmin. The purified APPI-72 was found to inhibit trypsin (Ki = 1.1 x 10(-10) M) and chymotrypsin (Ki = 5.8 x 10(-9) M) most strongly, and to inhibit leukocyte elastase (Ki = 7.9 x 10(-7) M) and several blood coagulation proteinases (Ki = 0.46-12 x 10(-7) M), but not urokinase or thrombin. The observed inhibition pattern was quite different from that of protease nexin I, one of serine proteinase inhibitors possessing neurite outgrowth activity. This suggests that the physiological roles of APPI are different from those of protease nexin I, and that APPI could not cause aberrant growth of neurite into the plaque. The presence of APPI having strong inhibitory activity in the brain might lead to the formation of amyloid deposits by preventing complete degradation of APPs.

• Yoshikawa K, Aizawa T, Maruyama K
• Neural differentiation increases expression of Alzheimer amyloid protein precursor gene in murine embryonal carcinoma cells.
• Biochem Biophys Res Commun. 1990; 171: 204-9
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• Neural differentiation of the embryonal carcinoma P19 cell line markedly increased the abundance of mRNA encoding Alzheimer amyloid beta/A4-protein precursor (APP). In P19 cells treated with retinoic acid, the abundance of mRNA encoding APP695, which lacks the protease inhibitor domain, reached a maximum on days 2-4 and decreased thereafter, whereas the abundances of mRNAs encoding APP751 and APP770, both possessing the protease inhibitor domain, slowly increased to reach higher levels than APP695 mRNA at later stages of neural differentiation. The induction of APP695 mRNA was consistent with the appearance of neurons in the P19 cultures. A high abundance of APP695 mRNA was also detected in mouse brain at a stage of the period of neuroblast formation. Thus, neural differentiation of P19 cells may present a suitable model for studying the regulation of APP gene expression during early differentiation of brain cells in vivo.

• Mita S, Schon EA, Herbert J
• Widespread expression of amyloid beta-protein precursor gene in rat brain.
• Am J Pathol. 1989; 134: 1253-61
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• The neuritic plaque is a characteristic finding in Alzheimer's disease. A major component of the plaque core is a 4.2 kd polypeptide, amyloid beta-protein (ABP), which is derived from the C-terminus of a larger precursor protein (ABPP). The authors have studied the transcription of ABPP mRNA in the adult rat brain by Northern analysis and in situ hybridization, and report that the ABPP gene gives rise to essentially the same multitranscript family of mRNAs as in the human, and that differential transcription patterns exist between brain and kidney. Morphologically, ABPP mRNA is expressed ubiquitously in neurons of the fore and hindbrain. ABPP transcripts also are present less frequently in occasional glial cells and at moderate to low frequency in nonneural cell types, namely, the choroid plexus epithelium, ependymal cells, and leptomeningeal membranes. Neuronal transcripts are most abundant in cerebral cortical layers II and V, the pyramidal cell layer of the hippocampus, the olfactory cortex, nucleus basis pontis, cranial nerve nuclei, and, significantly, in Purkinje cells and cerebellar granule cells. Because the cerebellum is relatively uninvolved in Alzheimer's disease, these findings suggest that high intraneuronal expression of ABPP may be a necessary but not sufficient requirement for plaque formation.

• Oltersdorf T et al.
• The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II.
• Nature. 1989; 341: 144-7
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• The A4 protein (or beta-protein) is a 42- or 43-amino-acid peptide present in the extracellular neuritic plaques in Alzheimer's disease and is derived from a membrane-bound amyloid protein precursor (APP). Three forms of APP have been described and are referred to as APP695, APP751 and APP770, reflecting the number of amino acids encoded for by their respective complementary DNAs. The two larger APPs contain a 57-amino-acid insert with striking homology to the Kunitz family of protease inhibitors. Here we report that the deduced amino-terminal sequence of APP is identical to the sequence of a cell-secreted protease inhibitor, protease nexin-II (PN-II). To confirm this finding, APP751 and APP695 cDNAs were over-expressed in the human 293 cell line, and the secreted N-terminal extracellular domains of these APPs were purified to near homogeneity from the tissue-culture medium. The relative molecular mass and high-affinity binding to dextran sulphate of secreted APP751 were consistent with that of PN-II. Functionally, secreted APP751 formed stable, non-covalent, inhibitory complexes with trypsin. Secreted APP695 did not form complexes with trypsin. We conclude that the secreted form of APP with the Kunitz protease inhibitor domain is PN-II.

• Yamada T, Sasaki H, Dohura K, Goto I, Sakaki Y
• Structure and expression of the alternatively-spliced forms of mRNA for the mouse homolog of Alzheimer's disease amyloid beta protein precursor.
• Biochem Biophys Res Commun. 1989; 158: 906-12
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• The human amyloid beta protein (BP) is a major constituent of the amyloid deposited in the brain of patients with Alzheimer's disease and is derived from a larger precursor protein (BPP). In human three alternatively-spliced forms of BPP mRNA were found and two of them were shown to encode a protease inhibitory activity. We have isolated the corresponding species of cDNA in mice and found that the inhibitor domain is highly conserved through mammalian evolution. The homology between human and mouse was 94.6%. Northern blot using specific probes showed that the mRNA for BPP with inhibitor domain was present in every tissue, particularly at a higher level in the kidney. On the other hand, that without inhibitor domain was found most abundantly in the brain but much less in the kidney and the intestine. These data suggest that the individual BPP mRNA species were produced in a tissue-specific manner in mouse as in the case of human.

• Van Nostrand WE et al.
• Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor.
• Nature. 1989; 341: 546-9
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• Protease nexin-II (PN-II) is a protease inhibitor that forms SDS-resistant inhibitory complexes with the epidermal growth factor (EGF)-binding protein, the gamma-subunit of nerve growth factor, and trypsin. The properties of PN-II indicate that it has a role in the regulation of certain proteases in the extracellular environment. Here we describe more of the amino-acid sequence of PN-II and its identity to the deduced sequence of the amyloid beta-protein precursor (APP). Amyloid beta-protein is present in neuritic plaques and cerebrovascular deposits in individuals with Alzheimer's disease and Down's syndrome. A monoclonal antibody against PN-II (designated mAbP2-1) recognized PN-II in immunoblots of serum-free culture medium from human glioblastoma cells and neuroblastoma cells, as well as in homogenates of normal and Alzheimer's disease brains. In addition, mAbP2-1 stained neuritic plaques in Alzheimer's disease brain. PN-II was a potent inhibitor of chymotrypsin with an inhibition constant Ki of 6 x 10(-10)M. Together, these data demonstrate that PN-II and APP are probably the same protein. The regulation of extracellular proteolysis by PN-II and the deposition of at least parts of the molecule in senile plaques is consistent with previous reports that implicate altered proteolysis in the pathogenesis of Alzheimer's disease.

• Xie YX, Herget T, Hallmayer J, Starzinski-Powitz A, Hossmann KA
• Determination of RNA content in postischemic gerbil brain by in situ hybridization.
• Metab Brain Dis. 1989; 4: 239-51
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• Brief periods of cerebral ischemia result in prolonged inhibition of protein synthesis. In CA1 sector of hippocampus inhibition is irreversible, leading to delayed death of pyramidal neurons. In order to study the possible role of gene transcription in this process, expression of four individual RNAs was investigated in the gerbil brain after 5 min of global cerebral ischemia by in situ hybridization with the following nucleic acid probes: plasmid pMr100 (ribosomal RNA sequences), plasma pAG82 (cytochrome c oxidase sequences), plasmid p629 (amyloid A4 precursor protein of Alzheimer's disease, pre-A4 protein), and plasmid pHF beta A-1 (beta-actin sequences). Cytochrome c oxidase mRNA and ribosomal RNA did not show any changes in expression up to 48 hr after ischemia. After longer recirculation times they gradually declined in the CA1 sector of hippocampus in parallel with the morphological manifestation of delayed neuronal death. The pre-A4 mRNA transiently decreased after 8 hr of recirculation of the CA1 sector but then recovered before it finally disappeared in parallel with delayed neuronal death. The beta-actin mRNA transiently appeared to increase after 8 hr of recirculation in the stratum radiatum of hippocampus but then also declined and disappeared when CA1 neurons began to disintegrate. The possible significance of these changes in the pathogenesis of ischemic neuronal damage is discussed.

• Johnstone EM, Chaney MO, Moore RE, Ward KE, Norris FH, Little SP
• Alzheimer's disease amyloid peptide is encoded by two exons and shows similarity to soybean trypsin inhibitor.
• Biochem Biophys Res Commun. 1989; 163: 1248-55
• Display abstract

• To better understand the processing of the Alzheimer disease amyloid precursor protein, we have cloned and sequenced that region of the human genome coding for the amyloid peptide. Two exons separated by a 6.2kb intron define this region. Characterization of the A4 peptide amino acid sequence shows similarity to the structure of soybean trypsin inhibitor (Kunitz). Our observation describes a different region of PreA4 than the previously characterized domain of larger amyloid precursor molecules PreA4 751 and 770(2). Moreover, the exon organization, Kunitz domain duplication and transmembrane location of A4 suggest that PreA4 is similar to growth factor precursors and thus may be processed similarly.

• Fukuchi K, Martin GM, Deeb SS
• Sequence of the protease inhibitor domain of the A4 amyloid protein precursor of Mus domesticus.
• Nucleic Acids Res. 1989; 17: 5396-5396

• Neve RL, Finch EA, Dawes LR
• Expression of the Alzheimer amyloid precursor gene transcripts in the human brain.
• Neuron. 1988; 1: 669-77
• Display abstract

• An alternate form of the Alzheimer amyloid protein precursor mRNA that encodes a protease inhibitor domain has recently been reported. Oligonucleotide probes that differentiate between the two mRNAs are used to describe the expression of each amyloid precursor transcript in the human brain. RNA blot analyses show that one of the mRNAs is expressed selectively in the nervous system, that the two messages display different regional distributions in the adult human brain, and that the expression of the two mRNAs is differentially affected in Down's syndrome brain and in Alzheimer's disease frontal cortex. In situ hybridization shows that the two transcripts display the same laminar distribution in the adult cortex but that the transcripts differ significantly in their levels of expression in pyramidal cells of the hippocampus.

• Salbaum JM, Weidemann A, Lemaire HG, Masters CL, Beyreuther K
• The promoter of Alzheimer's disease amyloid A4 precursor gene.
• EMBO J. 1988; 7: 2807-13
• Display abstract

• The promoter of the gene for the human precursor of Alzheimer's disease A4 amyloid protein (PAD gene) resembles promoters of housekeeping genes. It lacks a typical TATA box and shows a high GC content of 72% in a DNA region that confers promoter activity to a reporter gene in an in vivo assay. Transcription initiates at multiple sites. Sequences homologous to the consensus binding sites of transcription factor AP-1 and the heat shock control element binding protein were found upstream of the RNA start sites. Six copies of a 9-bp-long GC-rich element are located between positions -200 and -100. A protein--DNA interaction could be mapped to this element. The 3.8 kb of the 5' region of the PAD gene include two Alu-type repetitive sequences. These findings suggest that four mechanisms may participate in the regulation of the PAD gene and could be of relevance for the progression of amyloid deposition in Alzheimer's disease.

• Donnelly RJ, Rasool CG, Bartus R, Vitek S, Blume AJ, Vitek M
• Multiple forms of beta-amyloid peptide precursor RNAs in a single cell type.
• Neurobiol Aging. 1988; 9: 333-8
• Display abstract

• The longest open reading frames (ORFs) of three different cDNAs ([10, 12, 18, 26], and this report) contain the exact 42 amino acid (aa) sequence of the beta-amyloid peptide (BAP) which is selectively deposited in Alzheimer's diseased (AD) brains. Each of the three cDNAs for the putative amyloid peptide precursor (APP) has been cloned from a different cell type. Using an HL 60 library, we have cloned two of these three APP cDNAs from a single cell type. The sequences of the HL 60 cDNAs are identical to the APP 751 and to the APP 770 forms of APP cDNAs. Northern blots show that oligonucleotide probes drawn from unique regions of the APP 751 and APP 770 cDNAs both hybridize to 4.0 Kilobase (Kb) and to 1.6 Kb APP RNAs from HL 60 cells. In human adult brain, an oligonucleotide probe drawn from the unique region of the APP 751 cDNA hybridizes to a 3.5 Kb APP RNA. However, a DNA probe drawn from the BAP region, which is common to the 695, 751, and 770 forms of APP cDNAs, hybridizes to 3.5, 3.2 and 1.6 Kb APP RNAs. Taken together, these results show that at least two forms of APP RNAs can exist within a single cell type and that the diversity of possible APP RNAs and complexity of their expression may have been underestimated. Thus, in addition to identifying the cells which produce BAP, a new challenge consists of determining which form of forms of APP RNAs and hence APP proteins are associated with BAP deposition in AD and Down syndrome (DS).

• Zain SB, Salim M, Chou WG, Sajdel-Sulkowska EM, Majocha RE, Marotta CA
• Molecular cloning of amyloid cDNA derived from mRNA of the Alzheimer disease brain: coding and noncoding regions of the fetal precursor mRNA are expressed in the cortex.
• Proc Natl Acad Sci U S A. 1988; 85: 929-33
• Display abstract

• To gain insight into factors associated with the excessive accumulation of beta-amyloid in the Alzheimer disease (AD) brain, the present studies were initiated to distinguish between a unique primary structure of the AD-specific amyloid precursor mRNA vis a vis other determinants that may affect amyloid levels. Previous molecular cloning experiments focused on amyloid derived from sources other than AD cases. In the present work, we cloned and characterized amyloid cDNA derived directly from AD brain mRNA. Poly(A)+ RNA from AD cortices was used for the preparation of lambda gt11 recombinant cDNA libraries. An insert of 1564 nucleotides was isolated that included the beta-amyloid domain and corresponded to 75% of the coding region and approximately equal to 70% of the 3'-noncoding region of the fetal precursor amyloid cDNA reported by others. On RNA blots, the AD amyloid mRNA consisted of a doublet of 3.2 and 3.4 kilobases. In control and AD cases, the amyloid mRNA levels were nonuniform and were independent of glial-specific mRNA levels. Based on the sequence analysis data, we conclude that a segment of the amyloid gene is expressed in the AD cortex as a high molecular weight precursor mRNA with major coding and 3'-noncoding regions that are identical to the fetal brain gene product.

• Ito H, Kitaguchi N
• [Molecular cytogenetic study and chromosome abnormalities in Alzheimer's disease. Protease-inhibitory peptides and amyloid beta protein in Alzheimer's disease]
• Nippon Rinsho. 1988; 46: 1514-20

• Nukina N
• [Biochemistry study on brain pathology in Alzheimer's disease. Biochemical approach to the etiological mechanism]
• Nippon Rinsho. 1988; 46: 1475-83

• Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiri S, Ito H
• Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity.
• Nature. 1988; 331: 530-2
• Display abstract

• Alzheimer's disease is characterized by cerebral deposits of amyloid beta-protein (AP) as senile plaque core and vascular amyloid, and a complementary DNA encoding a precursor of this protein (APP) has been cloned from human brain. From a cDNA library of a human glioblastoma cell line, we have isolated a cDNA identical to that previously reported, together with a new cDNA which contains a 225-nucleotide insert. The sequence of the 56 amino acids at the N-terminal of the protein deduced from this insert is highly homologous to the basic trypsin inhibitor family, and the lysate from COS-1 cells transfected with the longer APP cDNA showed an increased inhibition of trypsin activity. Partial sequencing of the genomic DNA encoding APP showed that the 225 nucleotides are located in two exons. At least three messenger RNA species, apparently transcribed from a single APP gene by alternative splicing, were found in human brain. We suggest that protease inhibition by the longer APP(s) could be related to aberrant APP catabolism.

• Ishii T
• [Brain pathology in Alzheimer's disease. Progress in the immunohistochemistry study of amyloid senile plaques]
• Nippon Rinsho. 1988; 46: 1464-70

• Palmert MR et al.
• Amyloid protein precursor messenger RNAs: differential expression in Alzheimer's disease.
• Science. 1988; 241: 1080-4
• Display abstract

• In situ hybridization was used to assess total amyloid protein precursor (APP) messenger RNA and the subset of APP mRNA containing the Kunitz protease inhibitor (KPI) insert in 11 Alzheimer's disease (AD) and 7 control brains. In AD, a significant twofold increase was observed in total APP mRNA in nucleus basalis and locus ceruleus neurons but not in hippocampal subicular neurons, neurons of the basis pontis, or occipital cortical neurons. The increase in total APP mRNA in locus ceruleus and nucleus basalis neurons was due exclusively to an increase in APP mRNA lacking the KPI domain. These findings suggest that increased production of APP lacking the KPI domain in nucleus basalis and locus ceruleus neurons may play an important role in the deposition of cerebral amyloid that occurs in AD.

• Vitek MP et al.
• Absence of mutation in the beta-amyloid cDNAs cloned from the brains of three patients with sporadic Alzheimer's disease.
• Brain Res. 1988; 464: 121-31
• Display abstract

• Using an oligonucleotide probe, we isolated cDNA clones corresponding to the precursor of the beta-amyloid peptide (BAP) from brain libraries of 3 patients with sporadic Alzheimer's disease (AD). DNA sequencing showed that the largest cDNA clone encompasses 83% of the open reading frame proposed by Kang et al. to encode the BAP precursor (APP). cDNA clones from each of the 3 AD brain libraries were identical to the sequence of the APP-cDNAs cloned from normal adult human and fetal brain. An antisense-radiolabeled RNA copy of one of the AD clones detected a pattern of 3 gene transcripts measuring 3.5, 3.2 and 1.6 kilobases (kb) in both normal and AD brain RNAs. These data suggest that there are no mutations in or about the 42 amino acid (aa) sequence of BAP and that the accumulation of amyloid consistently found in AD may result from altered post-translational processing of APP.

• Tanaka S et al.
• Three types of amyloid protein precursor mRNA in human brain: their differential expression in Alzheimer's disease.
• Biochem Biophys Res Commun. 1988; 157: 472-9
• Display abstract

• Three types of amyloid protein precursor (APP) mRNA, produced by alternative splicing, were detected by Northern blotting in human brains, both control and Alzheimer's disease. These mRNAs encode APP695 consisting of 695 amino acids, APP751 harboring a 56 amino acid insert homologous to a Kunitz-type trypsin inhibitor inside APP695, and APP770 containing an additional 19 amino acid insert. Another possible APP mRNA which encodes "APP714" containing a 19 amino acid insert was not found in brain samples tested. Quantitative analysis revealed that, although the relative expression levels of the three mRNAs were variable among individuals, there was no remarkable change in expression of APP695 and APP751 mRNAs in Alzheimer's disease compared with control, but that APP770 mRNA level was elevated significantly in Alzheimer's disease.

• Johnson SA, Pasinetti GM, May PC, Ponte PA, Cordell B, Finch CE
• Selective reduction of mRNA for the beta-amyloid precursor protein that lacks a Kunitz-type protease inhibitor motif in cortex from Alzheimer brains.
• Exp Neurol. 1988; 102: 264-8
• Display abstract

• In poly(A) RNA from cerebral cortex obtained postmortem from victims of Alzheimer's disease (AD), an alternatively spliced mRNA for the amyloid precursor protein (APP-695 mRNA) was shown to be decreased by 65%. Another form (APP-751 mRNA) with an additional exon encoding a Kunitz-type (serine) protease inhibitor motif did not change appreciably (less than 30% decrease) in AD cortex. If this twofold increase in the APP-751 mRNA/APP-695 mRNA ratio results in a corresponding increase in the APP-751/APP-695 protein ratio, this would support the hypothesis that impaired proteolysis promotes the accumulation of abnormal proteins in the brain during AD. In the two previously known, major alternatively spliced forms of ca. 3.3 and 3.5 kb, we resolved doublet RNAs for each form that are consistent with sequence data showing multiple polyadenylation sites (J. Kang et al., 1987, Nature (London) 325, 733-736.). Smaller APP-related transcripts were also found (1.1, 1.0, 0.8, and 0.3 kb), some of which are selectively altered in AD.

• Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC
• Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease.
• Science. 1987; 235: 877-80
• Display abstract

• Four clones were isolated from an adult human brain complementary DNA library with an oligonucleotide probe corresponding to the first 20 amino acids of the beta peptide of brain amyloid from Alzheimer's disease. The open reading frame of the sequenced clone coded for 97 amino acids, including the known amino acid sequence of this polypeptide. The 3.5-kilobase messenger RNA was detected in mammalian brains and human thymus. The gene is highly conserved in evolution and has been mapped to human chromosome 21.

• Tanzi RE et al.
• Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus.
• Science. 1987; 235: 880-4
• Display abstract

• The amyloid beta protein has been identified as an important component of both cerebrovascular amyloid and amyloid plaques of Alzheimer's disease and Down syndrome. A complementary DNA for the beta protein suggests that it derives from a larger protein expressed in a variety of tissues. Overexpression of the gene in brain tissue from fetuses with Down syndrome (trisomy 21) can be explained by dosage since the locus encoding the beta protein maps to chromosome 21. Regional localization of this gene by both physical and genetic mapping places it in the vicinity of the genetic defect causing the inherited form of Alzheimer's disease.

• Bahmanyar S et al.
• Localization of amyloid beta protein messenger RNA in brains from patients with Alzheimer's disease.
• Science. 1987; 237: 77-80
• Display abstract

• The distribution of cells containing messenger RNA that encodes amyloid beta protein was determined in hippocampi and in various cortical regions from cynomolgus monkeys, normal humans, and patients with Alzheimer's disease by in situ hybridization. Both 35S-labeled RNA antisense and sense probes to amyloid beta protein messenger RNA were used to ensure specific hybridization. Messenger RNA for amyloid beta protein was expressed in a subset of neurons in the prefrontal cortex from monkeys, normal humans, and patients with Alzheimer's disease. This messenger RNA was also present in the neurons of all the hippocampal fields from monkeys, normal humans and, although to a lesser extent in cornu ammonis 1, patients with Alzheimer's disease. The distribution of amyloid beta protein messenger RNA was similar to that of the neurofibrillary tangles of Alzheimer's disease in some regions, but the messenger RNA was also expressed in other neurons that are not usually involved in the pathology of Alzheimer's disease.

• Yamada T, Sasaki H, Furuya H, Miyata T, Goto I, Sakaki Y
• Complementary DNA for the mouse homolog of the human amyloid beta protein precursor.
• Biochem Biophys Res Commun. 1987; 149: 665-71
• Display abstract

• The human amyloid beta protein is a major component of brain amyloid found in patients with Alzheimer's disease. As an initial step to understand the biological function of its precursor protein, we have isolated cDNA for the mouse homolog of the human beta protein precursor. Comparison of the predicted amino acid sequence with that of human revealed a quite high degree of homology (96.8%), and the calculated evolutionary rate of the mRNA at amino acid substitution site was relatively low (0.1 x 10(-9)/site/year). The mRNA was abundant in brain and kidney, and also detected in other tissues at low level. These results indicated that this protein is highly conserved through mammalian evolution and may be involved in a basic biological process(es).

• Goedert M
• Neuronal localization of amyloid beta protein precursor mRNA in normal human brain and in Alzheimer's disease.
• EMBO J. 1987; 6: 3627-32
• Display abstract

• Clones for the amyloid beta protein precursor gene were isolated from a cDNA library prepared from the frontal cortex of a patient who had died with a histologically confirmed diagnosis of Alzheimer's disease; they were used to investigate the tissue and cellular distribution of amyloid beta protein precursor mRNA in brain tissues from control patients and from Alzheimer's disease patients. Amyloid beta protein precursor mRNA was expressed in similar amounts in all control human brain regions examined, but a reduction of the mRNA level was observed in the frontal cortex from patients with Alzheimer's disease. By in situ hybridization amyloid beta protein precursor mRNA was present in granule and pyramidal cell bodies in the hippocampal formation and in pyramidal cell bodies in the cerebral cortex. No specific labelling of glial cells or endothelial cells was found. The same qualitative distribution was observed in tissues from control patients and from patients with Alzheimer's disease. Senile plaque amyloid thus probably derives from neurones. The tissue distribution of amyloid beta protein precursor mRNA and its cellular localization demonstrate that its expression is not confined to the brain regions and cells that exhibit the selective neuronal death characteristic of Alzheimer's disease.

• Mark JL
• Role of Alzheimer's protein is tangled.
• Science. 1987; 238: 1352-3

• Anderton BH
• Alzheimer's disease. Progress in molecular pathology.
• Nature. 1987; 325: 658-9

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