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PubMed2004

Frame-shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid beta40.

Frame-shifted amyloid precursor protein (APP(+1)), which has a truncated out-of-frame C-terminus, accumulates in the neuropathological hallmarks of patients with Alzheimer's disease pathology. To study a possible involvement of APP(+1) in the pathogenesis of Alzheimer's disease, we expressed APP695 and APP(+1) in the HEK293 cell-line and studied whether the processing of APP695 was affected. APP(+1) is a secretory protein, but high expression of APP695 and APP(+1) results in the formation of intracellular aggregate-like structures containing both proteins and Fe65, an adaptor protein that interacts with APP695. APP(+1) is shown to interact with APP695, suggesting that these structures consist of functional protein complexes. Such an interaction can also be anticipated in post-mortem brains of young Down's syndrome patients without any sign of neuropathology. Here we observed APP(+1) immunoreactivity in beaded fibres. Additional support for functional consequences on the processing of APP695 comes from a 1.4-fold increase in levels of secreted amyloid beta40 in cells co-expressing APP695 and APP(+1), although APP(+1) itself does not contain the amyloid beta sequence. Taken together, these data show that co-expression of APP695 and APP(+1) affects the processing of APP695 in a pro-amyloidogenic way and this could gradually contribute to Alzheimer's disease pathology, as has been implicated in Down's syndrome patients.

Adult↗
PubMed2006

Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease.

Oxidative stress is observed in Alzheimer's disease (AD) brain, including protein oxidation and lipid peroxidation. One of the major pathological hallmarks of AD is the brain deposition of amyloid beta-peptide (Abeta). This 42-mer peptide is derived from the beta-amyloid precursor protein (APP) and is associated with oxidative stress in vitro and in vivo. Mutations in the PS-1 and APP genes, which increase production of the highly amyloidogenic amyloid beta-peptide (Abeta42), are the major causes of early onset familial AD. Several lines of evidence suggest that enhanced oxidative stress, inflammation, and apoptosis play important roles in the pathogenesis of AD. In the present study, primary neuronal cultures from knock-in mice expressing mutant human PS-1 and APP were compared with those from wild-type mice, in the presence or absence of various oxidizing agents, viz, Abeta(1-42), H2O2 and kainic acid (KA). APP/PS-1 double mutant neurons displayed a significant basal increase in oxidative stress as measured by protein oxidation, lipid peroxidation, and 3-nitrotyrosine when compared with the wild-type neurons (p < 0.0005). Elevated levels of human APP, PS-1 and Abeta(1-42) were found in APP/PS-1 cultures compared with wild-type neurons. APP/PS-1 double mutant neuron cultures exhibited increased vulnerability to oxidative stress, mitochondrial dysfunction and apoptosis induced by Abeta(1-42), H2O2 and KA compared with wild-type neuronal cultures. The results are consonant with the hypothesis that Abeta(1-42)-associated oxidative stress and increased vulnerability to oxidative stress may contribute significantly to neuronal apoptosis and death in familial early onset AD.

Aldehydes↗
PubMed2007

Docosahexaenoic acid stabilizes soluble amyloid-beta protofibrils and sustains amyloid-beta-induced neurotoxicity in vitro.

Enrichment of diet and culture media with the polyunsaturated fatty acid docosahexaenoic acid has been found to reduce the amyloid burden in mice and lower amyloid-beta (Abeta) levels in both mice and cultured cells. However, the direct interaction of polyunsaturated fatty acids, such as docosahexaenoic acid, with Abeta, and their effect on Abeta aggregation has not been explored in detail. Therefore, we have investigated the effect of docosahexaenoic acid, arachidonic acid and the saturated fatty acid arachidic acid on monomer oligomerization into protofibrils and protofibril fibrillization into fibrils in vitro, using size exclusion chromatography. The polyunsaturated fatty acids docosahexaenoic acid and arachidonic acid at micellar concentrations stabilized soluble Abeta42 wild-type protofibrils, thereby hindering their conversion to insoluble fibrils. As a consequence, docosahexaenoic acid sustained amyloid-beta-induced toxicity in PC12 cells over time, whereas Abeta without docosahexaenoic acid stabilization resulted in reduced toxicity, as Abeta formed fibrils. Arachidic acid had no effect on Abeta aggregation, and neither of the fatty acids had any protofibril-stabilizing effect on Abeta42 harboring the Arctic mutation (AbetaE22G). Consequently, AbetaArctic-induced toxicity could not be sustained using docosahexaenoic acid. These results provide new insights into the toxicity of different Abeta aggregates and how endogenous lipids can affect Abeta aggregation.

Amyloid↗
PubMed1998

Cerebrospinal fluid levels of amyloid precursor protein and amyloid beta-peptide in Alzheimer's disease and major depression - inverse correlation with dementia severity.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive dementia that ultimately leads to death. Histopathological hallmarks of AD include brain amyloid deposits and neurofibrillary tangles. Major depression is a frequent diagnosis in every gerontopsychiatric clinic that sees patients with both cognitive and affective disorders. Many depressed patients, in fact, are clinically characterized by cognitive impairments. Thus, an assay that excludes - or confirms - probable AD in cognitively impaired patients is desirable. Such assays may use protein markers that are derived from such histopathologically relevant molecules as the amyloid precursor protein (APP) and its derivatives including the amyloid beta-peptides (Abeta). To evaluate the differential diagnostic properties of cerebrospinal fluid (CSF) Abeta and secreted soluble ectodomain (APPs), we quantitated CSF levels of these measures in AD patients and compared them to age-matched control patients with major depression. CSF levels of APPs and Abeta were similar in patients with AD or major depression, and the apolipoprotein E genotype had no influence on CSF levels of Abeta in AD patients. Measurement of Abeta peptide using a novel zinc/copper capture ELISA that detects aggregated Abeta peptides as well demonstrated similar levels in AD and major depression. In AD patients, CSF levels of total Abeta (Abeta1-40 plus Abeta1-42) were inversely correlated with a functional measure of dementia severity (NOSGER), suggesting that CSF levels of Abeta decrease with advancing severity of AD. Thus, CSF levels of Abeta are not useful for the differentiation of AD from major depression. However, CSF levels of Abeta reflect the severity of dementia and may be useful as biological markers of the stage of the disease.

Aged↗
PubMed1995

Beta-Amyloid peptide and amyloid precursor proteins in olfactory mucosa of patients with Alzheimer's disease, Parkinson's disease, and Down syndrome.

Dystrophic neurites are present in olfactory epithelium (OE) of patients with Alzheimer's disease (AD), Parkinson's disease (PD), and Down syndrome (DS) and occasionally in normal individuals. Cultured olfactory neuroblasts from AD patients generate carboxy terminal amyloid precursor protein (APP) fragments that contain beta-amyloid (A beta), but it is not known if deposits of A beta and/or APP fragments occur in the OE of individuals with or without AD, PD, or DS. To determine if A beta accumulates in the OE in situ, we probed postmortem samples of olfactory mucosa from patients with AD, PD, and AD (PD/AD), and DS and AD (DS/AD), as well as from controls, using polyclonal and monoclonal antibodies to A beta and flanking sequences in APPs. Samples of OE also were examined by thioflavin-S and electron microscopy. Labeling of A beta was observed in 10 of 12 AD cases, 2 of 3 PD/AD cases, 3 of 4 DS/AD cases, 3 of 10 adult controls, and 4 of 6 fetal cases. The A beta staining was seen in the basal third of the OE, in axons projecting through the lamina propria, and in metaplastic respiratory epithelium within the OE. Antibodies to other APP domains stained the OE of patients and controls. Thioflavin-S staining was present in the basal third of the OE of 8 of 9 AD patients and several PD/AD and DS/AD patients, but only in rare cells of 3 controls. Electron microscopy did not reveal amyloid fibrils in the OE.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMedDate not supplied

Colocalization of amino terminal and A4 (beta-amyloid) antigens in Alzheimer plaques: evidence for coordinated processing of the amyloid precursor protein.

The mechanism by which the A4 (beta-amyloid) domain of the Alzheimer amyloid precursor protein (APP) is deposited in plaques is unknown, and limited information is available concerning the extent to which other APP sites are associated with plaques. To address these issues, we prepared antiserum to a peptide adjacent to the N-terminus of the APP (referred to as N1) and examined its distribution in brain relative to A4 by double-immunostaining techniques. Anti-N1 localized to both neurons and glia in control and Alzheimer patients. In the Alzheimer brain, anti-N1 detected plaques. Quantitation revealed that 85% of thioflavin-positive plaques, and 91% of A4-positive plaques were also N1 positive. Double-staining methods directly demonstrated colocalization of distant APP sites. The data suggest that suggest that proposed mechanisms for amyloid deposition during plaque formation must take into account the extracytoplasmic domain, in addition to the A4 region, rather than be confined exclusively to the A4 site.

Aged↗
PubMed2005

Beta-secretase-cleaved amyloid precursor protein accumulates at actin inclusions induced in neurons by stress or amyloid beta: a feedforward mechanism for Alzheimer's disease.

Rod-like inclusions (rods), composed of actin saturated with actin depolymerizing factor (ADF)/cofilin, are induced in hippocampal neurons by ATP depletion, oxidative stress, and excess glutamate and occur in close proximity to senile plaques in human Alzheimer's disease (AD) brain (Minamide et al., 2000). Here, we show rods are found in brains from transgenic AD mice. Soluble forms of amyloid beta (Abeta(1-42)) induce the formation of rods in a maximum of 19% of cultured hippocampal neurons in a time- and concentration-dependent manner. Approximately one-half of the responding neurons develop rods within 6 h or with as little as 10 nM Abeta(1-42). Abeta(1-42) induces the activation (dephosphorylation) of ADF/cofilin in neurons that form rods. Vesicles containing amyloid precursor protein (APP), beta-amyloid cleavage enzyme, and presenilin-1, a component of the gamma-secretase complex, accumulate at rods. The beta-secretase-cleaved APP (either beta-C-terminal fragment of APP or Abeta) also accumulates at rods. These results suggest that rods, formed in response to either Abeta or some other stress, block the transport of APP and enzymes involved in its processing to Abeta. These stalled vesicles may provide a site for producing Abeta(1-42), which may in turn induce more rods in surrounding neurons, and expand the degenerative zone resulting in plaque formation.

Actins↗
PubMed1998

Islet amyloid-associated diabetes in obese A(vy)/a mice expressing human islet amyloid polypeptide.

We have previously shown that hemizygous transgenic mice expressing human islet amyloid polypeptide (hIAPP) in pancreatic beta-cells have no diabetic phenotype, whereas in the homozygous state, they developed severe, early-onset hyperglycemia associated with impaired insulin secretion and beta-cell death. We investigated the possibility that when the hemizygous mice are crossed onto an obese, insulin-resistant strain such as agouti viable yellow (A(vy)/a), they would exhibit a phenotype more akin to human type 2 diabetes. The hIAPP-expressing A(vy) males (TG-Y) displayed fasting hyperglycemia at 90 days of age and by 1 year progressed to severe hyperglycemia relative to their nontransgenic counterparts. Plasma insulin concentrations and pancreatic insulin content dropped 10- to 20-fold, suggesting severe impairment of beta-cell function. Histopathological findings revealed beta-cell degeneration and loss consistent with the drop in the plasma insulin concentration. In addition, large deposits of IAPP amyloid were present in TG-Y islets. We conclude that in transgenic mice expressing hIAPP, insulin resistance can induce overt, slow-onset diabetes associated with islet amyloid and decreased beta-cell mass.

Aging↗
PubMed2001

Identical amyloid precursor proteins in two breeds of chickens which differ in susceptibility to develop amyloid arthropathy.

Chickens (Gallus gallus domesticus) can suffer from AA amyloidosis featuring the joints as major targets of amyloid accumulation. Analysis of post-mortem recordings from commercial chickens revealed that amyloid arthropathy frequently occurred in brown layer chickens, but never in white layers. The suspected higher susceptibility of brown layers was confirmed experimentally by inducing amyloidosis with an arthropathic and amyloidogenic strain of E. faecalis. Sequence analysis of cDNA coding for SAA, the amyloid precursor protein, revealed that the SAA proteins are identical in both breeds, although some nucleotide differences existed in the untranslated regions of the mRNAs. The chicken SAA gene was found to be a single copy gene which comprises 4 exons. The first of these exons apparently occupies a conserved position and is not translated. Investigation of the affected joints using in situ hybridization demonstrated local SAA gene expression. It is concluded that the likelihood of an E. faecalis induced arthritis to progress to amyloidosis is breed-dependent, but is not a consequence of a more amyloidogenic SAA.

Amino Acid Sequence↗
PubMed1999

Effects of the amyloid precursor protein Glu693-->Gln 'Dutch' mutation on the production and stability of amyloid beta-protein.

Hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D), is a cerebral amyloidosis characterized by prominent vascular deposits and fatal haemorrhages. The disorder is caused by a point mutation in codon 693 of the gene encoding the amyloid precursor protein (APP), resulting in a Glu-->Gln amino acid substitution at position 22 of the amyloid beta-protein (Abeta) region. The pathogenetic mechanisms of HCHWA-D are unknown but could involve alterations in the proteolytic processing of APP and in amyloid fibril formation. We examined Abeta production and stability by using cultured human embryonic kidney 293 cells stably expressing wild-type or 'Dutch' APP. Radiosequencing and quantitative immunoprecipitation experiments showed that cells expressing Dutch APP secreted increased quantities of Abeta peptides beginning at Asp1, and of truncated peptides beginning at Val18 and Phe19. The ratio of levels of 4 kDa (Abeta) to 3 kDa (p3) peptides remained constant due to co-ordinate decreases in other peptide species. Novel truncated or elongated peptides were not observed. Pulse-chase experiments showed that the Dutch mutation did not affect the stability of the Abeta or p3 populations. These results are consistent with a disease process in which the Dutch mutation results in the production of Abeta peptides with enhanced propensities for fibrillogenesis, leading to accelerated vascular deposition and disease.

Amino Acid Sequence↗
PubMed2000

Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice.

Many neurodegenerative diseases are associated with the abnormal sequestration of disease-specific proteins in the brain, but the events that initiate this process remain unclear. To determine whether the deposition of the beta-amyloid peptide (Abeta), a key pathological feature of Alzheimer's disease (AD), can be induced in vivo, we infused dilute supernatants of autopsy-derived neocortical homogenates from Alzheimer's patients unilaterally into the hippocampus and neocortex of 3-month-old beta-amyloid precursor protein (betaAPP)-transgenic mice. Up to 4 weeks after the infusion there was no Abeta-deposition in the brain; however, after 5 months, the AD-tissue-injected hemisphere of the transgenic mice had developed profuse Abeta-immunoreactive senile plaques and vascular deposits, some of which were birefringent with Congo Red. There was limited deposition of diffuse Abeta also in the brains of betaAPP-transgenic mice infused with tissue from an age-matched, non-AD brain with mild beta-amyloidosis, but none in mice receiving extract from a young control case. Abeta deposits also were not found in either vehicle-injected or uninjected transgenic mice or in any nontransgenic mice. The results show that cerebral beta-amyloid can be seeded in vivo by a single inoculation of dilute AD brain extract, demonstrating a key pathogenic commonality between beta-amyloidosis and other neurodegenerative diseases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo beta-amyloidogenesis in the brain and may yield a more authentic animal model of Alzheimer's disease and other neurodegenerative disorders.

Adult↗
PubMed2002

Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice.

3-4-(2-Fluoro-alpha-methyl-[1,1'-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester (NCX-2216), a nitric oxide (NO)-releasing derivative of the cyclooxygenase-1-preferring nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen, dramatically reduced both beta-amyloid (Abeta) loads and Congo red staining in doubly transgenic (Tg) amyloid precursor protein plus presenilin-1 mice when administered at 375 ppm in diet between 7 and 12 months of age. This reduction was associated with a dramatic increase in the number of microglia expressing major histocompatibility complex-II antigen, a marker for microglial activation. In contrast, ibuprofen at 375 ppm in diet caused modest reductions in Abeta load but not Congo red staining, suggesting that the effects of this nonselective NSAID were restricted primarily to nonfibrillar deposits. We detected no effects of the cyclooxygenase-2-selective NSAID celecoxib at 175 ppm on amyloid deposition. In short-term studies of 12-month-old Tg mice, we found that the microglia-activating properties of NCX-2216 (7.5 mg small middle dot kg(-1) small middle dot d(-1), s.c.) were present after 2 weeks of treatment. Microglia were not activated by NCX-2216 in non-Tg mice lacking Abeta deposits, nor were microglia activated in Tg animals by flurbiprofen (5 mg small middle dot kg(-1) small middle dot d(-1)) alone. These data are consistent with the argument that activated microglia can clear Abeta deposits. We conclude that the NO-generating component of NCX-2216 confers biological actions that go beyond those of typical NSAIDs. In conclusion, NCX-2216 is more efficacious than ibuprofen or celecoxib in clearing Abeta deposits from the brains of Tg mice, implying potential benefit in the treatment of Alzheimer's dementia.

Administration, Oral↗
PubMed2002

[A sporadic case of late-onset familial amyloid polyneuropathy type I (transthyretin Met 30-associated familial amyloid polyneuropathy) inborn habitant of Ehime prefecture].

We reported a 62-year-old man of late-onset familial amyloid polyneuropathy type I(transthyretin Met 30-associated familial amyloid polyneuropathy) from Ehime Prefecture. There was no family history related to endemic Japanese foci (Nagano and Kumamoto foci). He demonstrated paraesthesia in the legs and mild autonomic symptoms at the age of 52. These symptoms gradually developed. Analysis of the transthyretin gene from his leucocytes demonstrated he had Met 30 transthyretin mutation. Therefore, he was diagnosed with late-onset familial amyloid polyneuropathy type I(FAP 1). In some families, asymptomatic carriers with the mutant transthyretin gene were diagnosed. In early stage, this patient's polyneuropathy and autonomic nervous system dysfunction were less serious than those of FAP 1 patients from endemic Japanese foci. These symptoms of this patient was slowly progressive. He hoped liver transplantation (brain death or living-related) treatment if possible. Now he became 68-year-old and bed-ridden.

Amyloid↗
PubMed2002

Increased extracellular amyloid deposition and neurodegeneration in human amyloid precursor protein transgenic mice deficient in receptor-associated protein.

The low-density lipoprotein receptor-related protein (LRP) is an abundant neuronal cell surface receptor that regulates amyloid beta-protein (Abeta) trafficking into the cell. Specifically, LRP binds secreted Abeta complexes and mediates its degradation. Previously, we have shown in vitro that the uptake of Abeta mediated by LRP is protective and that blocking this receptor significantly enhances neurotoxicity. To further characterize the effects of LRP and other lipoprotein receptors on Abeta deposition, an in vivo model of decreased LRP expression, receptor-associated protein (RAP)-deficient (RAP-/-) mice was crossed with human amyloid protein precursor transgenic (hAPP tg) mice, and plaque formation and neurodegeneration were analyzed. We found that, although the age of onset for plaque formation was the same in hAPP tg and hAPP tg/RAP-/- mice, the amount of amyloid deposited doubled in the hAPP tg/RAP-/- background. Moreover, these mice displayed increased neuronal damage and astrogliosis. Together, these results further support the contention that LRP and other lipoprotein receptors might be neuroprotective against Abeta toxicity and that this receptor might play an integral role in Abeta clearance.

Amyloid↗
PubMed1996

Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene.

Amyloid (A beta) deposition was investigated in cases of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch type, due to mutations in the amyloid precursor protein (APP) gene using the end-specific monoclonal antibodies BA27 and BC05 that recognize A beta 40 or A beta 42(43), respectively. In cases of APP717 mutation the predominant A beta species within plaques terminate at A beta 42(43) with relatively little A beta 40 being present. The total amount of A beta deposited as A beta 42(43) is significantly greater than in sporadic Alzheimer's disease, consistent with the suggestion that this mutation might influence the processing of APP so as to produce more of the highly aggregatable form, A beta 1-42. In cases of APP670/671 mutation the major peptide in plaques is also A beta 42(43), although the proportion of plaques containing A beta 40, and the total A beta load is similar to that in sporadic Alzheimer's disease. As in sporadic Alzheimer's disease, the vascular amyloid in APP670/671 and APP717 and in cases of hereditary cerebral hemorrhage with amyloidosis, Dutch type is predominantly A beta 40 in this latter disorder, however, parenchymal deposits are exclusively A beta 42(43). Although the various APP mutations may influence the type, quantity, and location of A beta deposited, the predominant, and possibly the initial, species deposited in the brain parenchyma is A beta 42(43).

Adult↗
PubMed1997

Phorbol esters affect multiple steps in beta-amyloid precursor protein trafficking and amyloid beta-protein production.

BACKGROUND: Amyloid beta-protein (A beta), the major constituent of amyloid deposits found in Alzheimer's disease, is derived from the beta-amyloid precursor protein (beta PP). Constitutive proteolysis by alpha-secretase and secretion of soluble beta PP (beta PPs) are stimulated by protein kinase C (PKC) activation, whereas A beta production and release are inhibited. The cellular mechanism that underlies the PKC-mediated down-regulation of A beta generation is unclear. Because endocytic processing of beta PP from the cell surface is a major pathway of A beta production, the effect of PKC activation by phorbol 12,13-dibutyrate (PDBu) on endocytic trafficking of beta PP was examined. MATERIALS AND METHODS: In this study, trafficking of beta PP was assayed in Chinese hamster ovary cells (CHO) cells stably transfected with full-length beta PP751. RESULTS: Treatment with PDBu resulted in a rapid and striking reduction of up to 80% in the amount of beta PP at the cell surface. This loss of cell-surface molecules could not be accounted for by changes in the trafficking of cell-surface beta PP molecules, as determined by a radiolabeled antibody assay. Rather, the decrease in beta PP was due primarily to a reduction in the sorting of beta PP to the cell surface. This alteration was correlated with accelerated intracellular alpha-secretase-mediated beta PP cleavage and accelerated beta PP trafficking in the exocytic pathway. CONCLUSIONS: The data suggest that the displacement of beta PP away from the cell surface after phorbol ester treatment reduces the substrate available for endocytic processing and in turn, results in the inhibition of A beta production.

Amino Acid Sequence↗
PubMed1997

Cerebrovascular smooth muscle cells internalize Alzheimer amyloid beta protein via a lipoprotein pathway: implications for cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is caused by the cerebrovascular deposition of Alzheimer amyloid beta protein (Abeta) and shows an increased incidence in carriers of the apolipoprotein E (APOE) epsilon4 genotype. To study the pathogenesis of CAA, primary cultures of human and canine smooth muscle cells from leptomeningeal vessels were incubated with fluorescein- and biotin-conjugated amyloid beta-protein. In the presence of human serum or cerebrospinal fluid, A beta1-40 and Abeta1-42 were rapidly internalized and appeared within endosomal and lysosomal vesicles. The accumulation of intracellular Abeta was enhanced by chloroquine and blocked by cycloheximide and brefeldin A and pretreatment with trypsin, suggesting that the internalization of Abeta occurs by receptor-mediated endocytosis. The internalization of Abeta was also inhibited by lipoprotein-deficient serum or by incubation with the 39-kd receptor-associated protein, indicating that Abeta is internalized via a receptor of the low-density lipoprotein receptor family. A lipoprotein pathway was confirmed by colocalization of cell surface-bound or internalized Abeta with APOE and low-density lipoprotein receptor-related protein. We propose a pathogenetic model of CAA, in which Abeta-APOE-complexes contained within the cerebrospinal fluid or the extracellular fluid of the brain are internalized and accumulated in cerebrovascular smooth muscle cells. Such a model could explain the preferential localization of CAA to the outer and middle layers of cortical and leptomeningeal arterioles, while indicating a mechanism by which the APOE genotype might determine the risk of CAA.

Amino Acid Sequence↗
PubMed1997

Amyloid beta-protein (Abeta) 1-40 but not Abeta1-42 contributes to the experimental formation of Alzheimer disease amyloid fibrils in rat brain.

Two major C-terminal variants ending at Val40 and Ala42 constitute the majority of amyloid beta-protein (Abeta), which undergoes postsecretory aggregation and deposition in the Alzheimer disease (AD) brain. To probe the differential pathobiology of the two Abeta variants, we used an in vivo paradigm in which freshly solubilized Abeta1-40 or Abeta1-42 was injected into rat brains, followed by examination using Congo red birefringence, Abeta immunohistochemistry, and electron microscopy. In the rat brain, soluble Abeta 1-40 and Abeta1-42 formed aggregates, and the Abeta1-40 but not the Abeta1-42 aggregates showed Congo red birefringence. Electron microscopy revealed that the Abeta1-40 aggregates contained fibrillar structures similar to the amyloid fibrils of AD, whereas the Abeta1-42 aggregates contained nonfibrillar amorphous material. Preincubation of Abeta1-42 solution in vitro led to the formation of birefringent aggregates, and after injection of the preincubated Abeta1-42, the aggregates remained birefringent in the rat brain. Thus, a factor or factors might exist in the rat brain that inhibit the fibrillar assembly of soluble Abeta1-42. To analyze the postsecretory processing of Abeta, we used the same in vivo paradigm and showed that Abeta1-40 and Abeta1-42 were processed at their N termini to yield variants starting at pyroglutamate, and at their C termini to yield variants ending at Val40 and at Val39. Thus the normal rat brain could produce enzymes that mediate the conversion of Abeta 1-40/1-42 into processed variants similar to those in AD. This experimental paradigm may facilitate efforts to elucidate mechanisms of Abeta deposition evolving into amyloid plaques in AD.

Alzheimer Disease↗