PubMed Health⌕ Search

Biomedical subjects

C Haass

Publications and source records attributed to C Haass.

At least 91 records · Page 5Linked to original sources
PubMed1997

Cellular expression and proteolytic processing of presenilin proteins is developmentally regulated during neuronal differentiation.

We have determined the expression of the Alzheimer's disease-associated proteins presenilin-1 and presenilin-2 in primary cultures of rat hippocampal neurons. Neurons highly express presenilin-1 and presenilin-2, whereas both proteins were not detected in astrocytes. Further, we have analyzed the subcellular localization and expression in rat hippocampal neurons during development. Although presenilin proteins were localized predominantly to the endoplasmic reticulum in nonneuronal cells transfected with presenilin cDNAs, in neurons, presenilin proteins were also found in compartments not staining with antibodies to grp78(BiP). Presenilin-1 and presenilin-2 were predominantly detected in vesicular structures within the somatodendritic compartment with much less expression in axons. Polarized distribution of presenilin-1 and presenilin-2 differs slightly, with more presenilin-2 expressed in axons compared with presenilin-1. Presenilin expression was found to be developmentally regulated. Presenilin expression strongly increased during neuronal differentiation until full morphological polarization and then declined. No full-length presenilin-1 or presenilin-2 could be detected within cell lysates. At early developmental stages the expected approximately 34-kDa N-terminal proteolytic fragment of presenilin-1 and the approximately 38-kDa fragment of presenilin-2 were detected. Later during differentiation we predominantly detected a approximately 38-kDa fragment for presenilin-1 and a approximately 42-kDa fragment for presenilin-2. By epitope mapping, we show that these slower migrating peptides represent N-terminal proteolytic fragments, cleaved C-terminal to the conventional site of processing. It is noteworthy that both presenilin-1 and presenilin-2 undergo alternative proteolytic cleavage at the same stage of neuronal differentiation. Regulation of presenilin expression and proteolytic processing might have implications for the pathological as well as the biological function of presenilins during aging in the human brain.

Animals↗
PubMed1997

Enhanced release of secreted form of Alzheimer's amyloid precursor protein from PC12 cells by nicotine.

There is mounting evidence indicating that overexpression or aberrant processing of amyloid precursor protein (betaAPP) is causally related to Alzheimer's disease. betaAPP is principally cleaved within the amyloid beta protein domain to release a large soluble ectodomain (betaAPPs) that has been known to have a wide range of trophic and protective functions. Activation of phospholipase C-coupled receptors has been shown to increase the release of betaAPPs through protein kinase C and calcium. Here we have examined whether nicotine can modulate the expression and processing of betaAPP in PC12 cells. Treatment of PC12 cells with nicotine increased the release of a carboxyl-terminally truncated, secreted form of betaAPP into the conditioned medium without affecting the expression level of betaAPP mRNA. The effect of nicotine on the secretion of betaAPPs is concentration (>50 microM)- and time (>2 hr)-dependent and attenuated by cotreatment with either mecamylamine, a specific nicotinic receptor antagonist, or EGTA, a calcium chelator, indicating calcium entry through the neuronal nicotinic acetylcholine receptor is essential in enhanced betaAPPs release by nicotine. However, nicotine did not significantly change the amyloid beta protein secretion from Swedish mutant betaAPP-transfected PC12 cells. These results imply that nicotinic receptor agonist might be beneficial in the treatment of Alzheimer's disease by not only supplementing the deficient cholinergic neurotransmission but also stimulating the release of betaAPPs.

Amyloid beta-Protein Precursor↗
PubMed1996

Degradation of amyloid beta-protein by a serine protease-alpha2-macroglobulin complex.

Progressive cerebral deposition of the amyloid beta-peptide (Abeta) is an early and constant feature of Alzheimer's disease. Abeta is derived by proteolysis from the beta-amyloid precursor protein. beta-Amyloid precursor protein processing and the generation of Abeta have been extensively characterized, but little is known about the mechanisms of degradation of this potentially neurotoxic peptide. We identified and purified a proteolytic activity in culture medium that can degrade secreted Abeta but not larger proteins in the medium. Detection of the activity in conditioned medium required the presence of fetal bovine serum and the passage of the cells with a pancreatic trypsin preparation. Its inhibitor profile showed that the activity was a serine protease other than trypsin or chymotrypsin. The protease occurs as a stable approximately 700-kDa complex with the inhibitor, alpha2-macroglobulin (alpha2M), that retains activity against small substrates such as Abeta. Its NH2-terminal sequence suggests that the protease is previously unidentified. Our results indicate that the Abeta-degrading protease we have detected is a non-trypsin component of a pancreatic trypsin preparation or else derives from a zymogen in serum that is activated by a protease in the latter preparation. Because Abeta-bearing plaques in Alzheimer's disease brain contain both alpha2M and receptors of alpha2M-protease complexes, the same or a similar alpha2M-protease complex could arise in vivo and play a role in Abeta clearance.

Amino Acid Sequence↗
PubMed1996

The role of APP processing and trafficking pathways in the formation of amyloid beta-protein.

The amyloid beta-protein (A beta) is a proteolytic fragment of the beta-amyloid precursor protein (beta APP). We previously reported the constitutive secretion of A beta peptides from a variety of cells expressing beta APP under normal culture conditions. These endogenously produced A beta peptides have heterogeneous N- and C-termini that vary as a function of beta APP missense mutations. Treatment of A beta-secreting cells with agents that alter intravesicular pH showed that an acidic compartment is required for proper A beta generation. One such compartment appears to be the endosome. Immunolabeling of cell-surface beta APP in living neurons and non-neuronal cells directly demonstrated the endocytosis of the protein and its rapid recycling (within 5-10 minutes) to the cell surface, as well as the trafficking of some beta APP to lysosomes. Expression of beta APP with various deletions of the cytoplasmic domain, including the NPTY motif, leads to decreased internalization and an associated decrease in the production of A beta peptides that begin at the usual asp1 start site. These and other data suggest that A beta production begins with cleavage of beta APP by a still unknown protease(s) (beta-secretase[s]) at the met-asp bond proceeding the A beta N-terminus and that this occurs in part in early endosomes. To characterize the substrate requirements of beta-secretase, beta APP was mutagenized by placing stop codons within or at the end of the transmembrane domain or substituting other amino acids for the wild-type met and asp at the P1 and P1' positions. These experiments showed that proper beta-secretase cleavage requires the precursor to be membrane-anchored and is highly sequence specific; most substitutions at met or asp substantially decrease A beta production. Analogous mutagenesis experiments around the A beta C-terminus revealed that the unknown protease(s) cleaving here ("gamma-secretase[s]") does not show such specificity. Cells secreting A beta may also be useful for examining the critical issue of the aggregation of A beta into its neurotoxic polymeric form under physiological conditions. In this regard, we have found that beta APP-expressing CHO cells show aggregation of > or = 10-20% of their secreted A beta peptides into SDS-stable dimers, trimers and sometimes tetramers under normal culture conditions. The identity of these small multimers was confirmed by extensive immunochemical characterization and radiosequencing. They are present at approximately 100-500 pM levels in conditioned medium of CHO transfectants. Using this endogenous A beta aggregating system, we have begun to examine variables that influence aggregation and compounds which may retard it. In conclusion, studies of the regulation of A beta production and aggregation in cell culture can provide information under physiological conditions that can complement analyses of these processes in vivo.

Amyloid beta-Peptides↗
PubMed1996

The molecular significance of amyloid beta-peptide for Alzheimer's disease.

Alzheimer's disease is the most common form of dementia. Although the majority of the cases occur sporadically, in some rare cases Alzheimer's disease is genetically inherited. Pathologically, Alzheimer's disease is characterized by the accumulation of senile plaques with-in the extracellular space of brain regions known to be important for intellectual functions. In addition to senile plaques, deposits of identical biochemical composition are found in the walls of meningeal and cerebral blood vessels. Senile plaques are surrounded by degenerating neurons indicating a toxic interference of amyloid plaques with neurons. The major component of senile plaques is the 4kDa amyloid beta-peptide. This peptide has been shown to exhibit neurotoxic properties when added to cultured neurons, or injected into rat brains. Amyloid beta-peptide is derived from a high molecular weight precursor, the beta-amyloid precursor protein, by proteolytic processing. Mutations responsible for the early onset of Alzheimer's disease in some families are found within the gene coding for the beta-amyloid precursor protein. These mutations strongly influence the generation of amyloid beta-peptide resulting in a significant overproduction of the peptide or the generation of elongated forms which are known to aggregate and precipitate much faster. Moreover, mutations found in other genes known to cause early onset of Alzheimer's disease have been shown to interfere directly with the production or precipitation of amyloid beta-peptide.

Alzheimer Disease↗
PubMed1996

Inhibition of amyloid beta-protein production in neural cells by the serine protease inhibitor AEBSF.

Cerebral deposition of amyloid beta protein (A beta) is an early and critical feature of Alzheimer's disease. A beta production requires the proteolytic release of A beta from the beta-amyloid precursor protein (beta APP). Thus, inhibition of A beta release is a prime therapeutic goal. Here, we show that the broad spectrum, irreversible serine protease inhibitor, AEBSF, inhibits the constitutive production of A beta in five different human cell lines, both neural and nonneural. AEBSF also stabilizes full-length beta APP and enhances alpha-secretion, as shown by an increase in the proteolytic derivative, alpha-APPS. Further, we demonstrate that the inhibitory effect of AEBSF is specific for A beta proteins starting at Aspartate 1, suggesting that AEBSF directly inhibits beta-secretase, the Methionine-Aspartate (Met-Asp)-cleaving enzyme. These results indicate that specific inhibition of this A beta-generating protease is possible in living human neural cells and provide information about the characteristics of this as yet unidentified enzyme.

Amino Acid Sequence↗
PubMed1996

Presenile because of presenilin: the presenilin genes and early onset Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder characterized by the massive and invariant accumulation of amyloid plaques in the brains of affected patients. In many cases Alzheimer's disease occurs in the absence of a prior history of the disease in other family members and is designated as sporadic, whereas in approximately 10% of patients, dominantly transmitted mutations within one of three genes are found. A few mutations have been identified within the gene encoding the beta-amyloid precursor protein; however, these mutations account for only about 1-3% of cases with familial Alzheimer's disease. In the majority of autosomal dominant cases (40-50%), mutations have been found in a gene localized to chromosome 14. The responsible gene, now called presenilin-1, has recently been identified and shown to encode a putative seven transmembrane domain protein. Surprisingly, a second highly homologous gene (named presenilin-2) was cloned shortly thereafter. It is localized on human chromosome 1 and is also involved in a small number of cases with familial Alzheimer's disease. Early data suggest that mutations found within the two genes cause early onset Alzheimer's disease by influencing the proteolytic processing of amyloid beta-peptide in a pathological manner.

Adult↗
PubMed1996

The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of extracellular senile plaques composed of amyloid beta-peptide (A beta). Whereas most cases of AD occur sporadically, about 10% of AD cases are inherited as a fully penetrant autosomal dominant trait. Mutations in the recently cloned Presenilin genes (PS-1 and PS-2) are by far the most common cause of early onset familial AD. MATERIALS AND METHODS: Cellular expression of endogenous and overexpressed PS proteins was analyzed by immunocytochemistry and metabolic labeling followed by immunoprecipitation. In vivo phosphorylation sites of PS proteins were analyzed by extensive mutagenesis. RESULTS: PS-1 as well as PS-2 proteins were localized predominantly within the endoplasmic reticulum (ER). However, small amounts of the PS proteins were detected within the Golgi compartment, where they colocalize with the beta-amyloid precursor protein (beta APP). The PS-2 protein was found to be highly phosphorylated, whereas very little phosphorylation was observed for PS-1. The selective phosphorylation of PS-2 occurs exclusively on serine residues. In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. CONCLUSIONS: The majority of PS proteins were detected in the ER where little if any proteolytic processing of beta APP was reported. ER retention of PS proteins might occur by intramolecular aggregation. Small amounts of PS proteins were also detected in the Golgi where they colocalized with beta APP. This might suggest that potential interactions between PS proteins and beta APP could occur within the Golgi. Selective phosphorylation of PS-2 proteins within the acidic domain missing in PS-1 indicates differences in the biological functions and regulation of the two highly homologous proteins.

Alzheimer Disease↗
PubMed1995

Lysosomal processing of amyloid precursor protein to A beta peptides: a distinct role for cathepsin S.

To investigate the potential contribution of the lysosomal compartment in the processing of amyloid precursor protein (APP) to amyloid beta-peptides (A beta s), we stably overexpressed a series of lysosomal proteases (the cysteine proteases, cathepsins B, L and S, and the aspartic protease, cathepsin D) in a human kidney epithelial cell line (293) transfected to express high levels of beta APP. Preliminary experiments indicated that 293 cells endogenously synthesize cathepsins B, L and D, but not cathepsin S. A beta secretion was assessed by immunoprecipitation and ELISA and found to be increased approximately 2-fold following cathepsin S expression, but to be unchanged (cathepsins B, L) or decreased (cathepsin D) in the other double transfectants. E-64d, an inhibitor of lysosomal cysteine proteases, significantly reduced A beta secretion by the cathepsin S transfectants, but had no effect on cells expressing the other proteases. Radiosequencing of A beta secreted by cathepsin S-expressing cells revealed that a previously unreported variant beginning at Met -1 (relative to the most common A beta N-terminus, Asp -1) accounted for most of the increase in A beta secretion. Immunostaining of human brain sections revealed cathepsin S in cortical neurons and glia in samples of brain from patients with Alzheimer's disease. These results provide evidence in living cells for a pathway in which cathepsin S generates A beta from amyloidogenic fragments of beta APP in the endosomal/lysosomal compartment. This pathway appears to be inducible, distinct from a constitutive pathway used by 293 and other cells to generate A beta, and may be relevant to the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed1995

The vacuolar H(+)-ATPase inhibitor bafilomycin A1 differentially affects proteolytic processing of mutant and wild-type beta-amyloid precursor protein.

We analyzed the effect of the vacuolar H(+)-ATPase inhibitor bafilomycin A1 (bafA1) on the processing of beta-amyloid precursor protein (beta APP). In kidney 293 cells stably transfected with the wild-type beta APP cDNA, bafA1 caused a stabilization of mature beta APP and its 10-kDa COOH-terminal fragment. Moreover, it caused a 2-3-fold increase in secretion of soluble APP and amyloid-beta protein (A beta). Interestingly, bafA1 treatment of cells transfected with a mutant beta APP isoform that occurs in a Swedish kindred with familial Alzheimer's disease resulted in a decrease of A beta production and no increase of soluble APP secretion. Identical results were obtained when the effect of bafA1 was analyzed on fibroblasts derived from affected versus unaffected members of the Swedish family. These data demonstrate a differential effect of bafA1 on the production of A beta derived from wild-type or Swedish mutant beta APP. Radiosequencing of A beta derived from bafA1-treated cells expressing wild-type beta APP revealed a marked increase of A beta peptides starting at amino acids phenylalanine 4 and valine -3 and a relative decrease of A beta molecules beginning at the typical NH2 terminus of aspartate 1. Cells transfected with the Swedish mutation and treated with bafA1 did not produce these alternative A beta peptides, so that bafA1 treatment resulted in a decrease of A beta starting at aspartate 1. Our data indicate that multiple proteases are able to cleave A beta at or near its NH2 terminus. Inhibition of the protease cleaving at aspartate 1 by bafA1 and perhaps other similar agents can result in an increase of alternatively cleaved peptides.

Alzheimer Disease↗
PubMed1995

The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway.

Several missense mutations causing early-onset Alzheimer's disease (AD) have been described in the gene coding for the beta-amyloid precursor protein (beta APP). A double mutation found in a Swedish family is located before the amyloid beta-peptide (A beta) region of beta APP and results in the increased production and secretion of A beta. Here we show that the increased production of A beta results from a cellular mechanism, which differs substantially from that responsible for the production of A beta from wild-type beta APP. In the latter case, A beta generation requires reinternalization and recycling of beta APP. In the case of the Swedish mutation the N-terminal beta-secretase cleavage of A beta occurs in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurs in the same compartment as the alpha-secretase cleavage, which normally prevents A beta production, explaining the increased A beta generation by a competition between alpha- and beta-secretase.

Age of Onset↗
PubMed1995

Polarized sorting of beta-amyloid precursor protein and its proteolytic products in MDCK cells is regulated by two independent signals.

Progressive cerebral deposition of the amyloid (A beta) beta-protein is an early and invariant feature of Alzheimer's disease. A beta is derived by proteolysis from the membrane-spanning beta-amyloid precursor protein (beta APP). beta APP is processed into various secreted products, including soluble beta APP (APPs), the 4-kD A beta peptide, and a related 3-kD peptide (p3). We analyzed the mechanisms regulating the polarized basolateral sorting of beta APP and its proteolytic derivatives in MDCK cells. Deletion of the last 32 amino acids (residues 664-695) of the beta APP cytoplasmic tail had no influence on either the constitutive approximately 90% level of basolateral sorting of surface beta APP, or the strong basolateral secretion of APPs, A beta, and p3. However, deleting the last 42 amino acids (residues 654-695) or changing tyrosine 653 to alanine altered the distribution of cell surface beta APP so that approximately 40-50% of the molecules were inserted apically. In parallel, A beta was now secreted from both surfaces. Surprisingly, this change in surface beta APP had no influence on the basolateral secretion of APPs and p3. This result suggests that most beta APP molecules which give rise to APPs in MDCK cells are cleaved intracellularly before reaching the surface. Consistent with this conclusion, we readily detected intracellular APPs in carbonate extracts of isolated membrane vesicles. Moreover, ammonium chloride treatment resulted in the equal secretion of APPs into both compartments, as occurs with other non-membranous, basolaterally secreted proteins, but it did not influence the polarity of cell surface beta APP. These results demonstrate that in epithelial cells two independent mechanisms mediate the polarized trafficking of beta APP holoprotein and its major secreted derivative (APPs) and that A beta peptides are derived in part from beta APP holoprotein targeted to the cell surface by a signal that includes tyrosine 653.

Amino Acid Sequence↗
PubMed1995

The lysosomal cysteine protease, cathepsin S, is increased in Alzheimer's disease and Down syndrome brain. An immunocytochemical study.

Expression of cathepsin (cat) S, a lysosomal cysteine protease, has recently been shown to cause an increase in production of amyloid beta-peptides in transfected human cells. In this study, we examined the presence and localization of cat S by immunocytochemistry in 21 control, 24 Alzheimer's disease (AD), and 10 Down syndrome (DS) postmortem brains. An antiserum to a human cat S fusion protein was affinity purified and its specificity confirmed by abolition of immunoreactivity after adsorption with cat S but not cat L fusion protein. A small minority of control cases showed light, focal staining of scattered cortical neurons. Many control cases, as well as most AD and DS cases, showed prominent staining of vascular smooth muscle cells, particularly in leptomeningeal vessels. Both AD and DS brain tissue showed increased immunoreactivity in a subset of neocortical and hippocampal neurons and glia. Cat S immunoreactivity occurred in a granular, cytoplasmic pattern in some neurons or in a more dense staining pattern in certain neurofibrillary tangle-bearing neurons. Cat S-positive neurons were also present in amygdala and basal forebrain in AD brains. A subset of astrocytes were immunoreactive with the cat S antibody in AD and DS but not in control brains. In rare AD cases, cat S immunostaining was observed in astrocytes in the periphery of amyloid-beta-containing plaques. These results suggest that cat S is up-regulated in AD and DS brain. The association of cat S immunoreactivity with tangle-bearing neurons, astrocytes, and rare senile plaques implies a role for altered cat S activity in the pathogenesis of AD.

Adult↗
PubMed1994

Metabolism of the "Swedish" amyloid precursor protein variant in Madin-Darby canine kidney cells.

The 4-kDa beta-amyloid peptide (A beta), a major constituent of parenchymal amyloid deposits in Alzheimer's disease, is derived from larger amyloid precursor proteins (APP). We have examined the metabolism of APP in Madin-Darby canine kidney cells stably transfected with cDNA encoding either wild-type human APP-695 or human APP-695 that harbors the Swedish double mutation associated with familial early-onset Alzheimer's disease. Although approximately 90% of total soluble APP secreted from wild-type cells is secreted basolaterally following cleavage at the alpha-secretase site, soluble derivatives cleaved near or at the amino terminus of A beta (presumably the "beta-secretase" site) are preferentially secreted into the apical compartment of SWE cells. Concomitantly, levels of a specific A beta-containing carboxyl-terminal fragment are elevated in SWE cell lysates. Using domain-specific biotinylation and release assays, we failed to detect a beta-secretase-generated soluble derivative (APPs beta) released from the surface of SWE cells. However, APPs beta can be detected in SWE cell lysates, consistent with "beta-secretase" cleavage occurring in an intracellular compartment. Finally, we demonstrate that A beta is secreted into the basolateral compartment of SWE cells and that the majority of these A beta-related species contains an amino-terminal aspartate residue (+1).

Amino Acid Sequence↗
PubMed1994

Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the extracellular deposition of amyloid beta-protein (A beta), a molecule produced by post-translational processing of the beta-amyloid precursor protein (beta APP). Mutations within the gene encoding beta APP have been linked to early onset forms of AD, but the pathogenetic mechanism(s) producing the phenotype are unknown. We analyzed the effects on beta APP processing in vitro of a naturally occurring Ala-->Gly mutation at position 692 of beta APP770 (A692G) (Hendriks, L., Duijin, C., Cras, P., Cruts, M., van Hul, W., van Harskamp, F., Warren, A., McInnis, M., Antonarakis, S., Martin, J.-J., Hofman, A., and van Broeckhoven, C. (1992) Nature Genet. 1, 218-221), as well as the effects of five genetically engineered mutations at or near this site. Substitution of glycine or proline for Ala692, or for Phe690, produced relative increases in secretion of A beta and relative decreases in secretion of the p3 peptide(s) arising after alpha-secretase generation of soluble APP (APPs). The Phe690-->Pro substitution also resulted in the synthesis of truncated APPs molecules. The structurally conservative substitutions Ala692-->Val and Phe690-->Tyr did not exhibit these effects. Certain of the substitutions also resulted in the production of a minor peptides, previously undescribed in vitro, beginning at Ala2, Lys16, and Phe19 of A beta. These data show that beta APP mutations carboxyl-terminal to alpha-secretase and beta-secretase cleavage sites can exert strong control over beta APP processing. Increased secretion of A beta may accelerate amyloidogenesis by providing more precursors for aggregation. It is also possible that truncated A beta peptides resulting from several of these mutations may accelerate amyloidogenesis through self-aggregation and/or seeding the fibrillogenesis of longer, more abundant A beta species.

Alanine↗
PubMed1994

Polarized secretion of beta-amyloid precursor protein and amyloid beta-peptide in MDCK cells.

The beta-amyloid precursor protein (beta APP) is a widely expressed integral membrane protein that is proteolytically processed to yield several secreted derivatives, including soluble APP (APPs), the 4-kDa amyloid beta-peptide (A beta), and a related 3-kDa peptide (p3). To understand beta APP trafficking and processing, we analyzed the sorting of beta APP in Madin-Darby canine kidney (MDCK) cells, an epithelial cell known to possess physiologically distinct apical and basolateral plasma membranes. Processing of beta APP resulted in highly polarized secretion of APPs. More than 90% of APPs was detected in the basolateral compartment, and less than 10% was found in the apical compartment. This was associated with a preferential localization of beta APP on the basolateral cell surface. Activation of protein kinase C, which is known to enhance the secretion of APPs, did not change the polarity of APPs release but significantly increased the amount secreted. A beta and p3 peptides were also secreted predominantly basolaterally. In addition, MDCK cells secreted a truncated form of A beta beginning at Arg-5. These data show that the proteolytic processing products of beta APP undergo polarized secretion. Moreover, the results suggest that the amyloidogenic A beta peptide is generated following the polarized sorting of beta APP. The polarized basolateral secretion of A beta in these epithelial cells provides a potential mechanism for the accumulation of A beta in the abluminal basement membrane of brain microvessels during Alzheimer disease.

Amino Acid Sequence↗
PubMed1993

Activation of protein kinase C inhibits cellular production of the amyloid beta-protein.

The 39-43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cerebral plaques and blood vessels in Alzheimer's disease (AD), is released by cultured human cells during normal metabolism. Here we show that agents which activate protein kinase C or otherwise enhance protein phosphorylation caused a substantial decrease in A beta production in vitro. Protein kinase C activation also markedly decreased A beta release from cells that express mutant forms of the beta-amyloid precursor protein genetically linked to familial AD. Inhibition of A beta secretion could also be effected by direct stimulation of m1 muscarinic acetylcholine receptors with carbachol. These results demonstrate that activation of the protein kinase C signal transduction pathways down-regulates the generation of the amyloidogenic A beta peptide. Pharmacologic agents that activate this system, including a variety of first messengers, could potentially slow the development or growth of some A beta plaques during the early stages of AD.

Amino Acid Sequence↗