Biomedical subjects

Chera Esh

Publications and source records attributed to Chera Esh.

10 recordsLinked to original sources

PubMed2006

Circle of Willis atherosclerosis: association with Alzheimer's disease, neuritic plaques and neurofibrillary tangles.

The role of intracranial atherosclerosis in Alzheimer's disease (AD) has been a subject of debate since the first decade of the last century. The initial "vascular hypothesis" of AD was rejected after a series of mid-twentieth century gross anatomical postmortem studies that showed an inconstant relationship between intracranial atherosclerosis and senile dementia. These early studies did not utilize statistical methods, however, and the investigators did not appear to consider the possibility that intracranial atherosclerosis might have a probabilistic, rather than an absolute, effect on AD risk. Recent studies by three independent groups have found a significant statistical association between postmortem measures of circle of Willis atherosclerosis and AD. The present study was undertaken to further address the validity of this association in a large autopsy series, including cases diagnosed neuropathologically with vascular dementia (VaD) and non-AD dementias. Postmortem gross anatomical grading of circle of Willis atherosclerosis was performed in 397 subjects classified by neuropathological diagnosis, including 92 non-demented elderly controls, 215 with AD, 30 with VaD and 60 with non-AD dementias. Circle of Willis atherosclerosis was more severe in subjects with AD and VaD than in control subjects, while it was equivalent between control subjects and subjects with non-AD dementias. Increasing atherosclerotic grade increased the odds ratios (OR) for the diagnoses of both AD and VaD and also increased the ORs for both increased neuritic plaque density and higher Braak neurofibrillary tangle stage. The significance of these associations was retained after consideration of the effects of age, gender and the apolipoprotein E-epsilon4 allele. The results suggest that the statistical association between intracranial atherosclerosis and AD is not an artifact of diagnostic misclassification or of unequal distribution of the apolipoprotein E-epsilon4 allele.

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PubMed2005

Altered APP processing in PDAPP (Val717 --> Phe) transgenic mice yields extended-length Abeta peptides.

Central to the pathology of Alzheimer's disease (AD) is the profuse accumulation of amyloid-beta (Abeta) peptides in the brain of affected individuals, and several amyloid precursor protein (APP) transgenic (Tg) mice models have been created to mimic Abeta deposition. Among these, the PDAPP Tg mice carrying the familial AD APP 717 Val --> Phe mutation have been widely used to test potential AD therapeutic interventions including active and passive anti-Abeta immunizations. The structure and biochemistry of the PDAPP Tg mice Abeta-related peptides were investigated using acid and detergent lysis of brain tissue, ultracentrifugation, FPLC, HPLC, enzymatic and chemical cleavage of peptides, Western blot, immunoprecipitation, and MALDI-TOF and SELDI-TOF mass spectrometry. Our experiments reveal that PDAPP mice produce a variety of C-terminally elongated Abeta peptides in addition to Abeta n-40 and Abeta n-42, as well as N-terminally truncated peptides, suggesting anomalous proteolysis of both APP and Abeta. Important alterations in the overall APP degradation also occur in this model, resulting in a striking comparative lack of CT83 and CT99 fragments, which may be inherent to the strain of mice, a generalized gamma-secretase failure, or the ultimate manifestation of the overwhelming amount of expressed human transgene; these alterations are not observed in other strains of APP Tg mice or in sporadic AD. Understanding at the molecular level the nature of these important animal models will permit a better understanding of therapeutic interventions directed to prevent, delay, or reverse the ravages of sporadic AD.

Amino Acid Sequence↗

PubMed2005

RAGE and amyloid beta interactions: atomic force microscopy and molecular modeling.

In the AD brain, there are elevated amounts of soluble and insoluble Abeta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Abeta to soluble RAGE inhibits further aggregation of Abeta peptides, while membrane bound RAGE-Abeta interactions elicit activation of the NF-kappaB transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with Abeta, is a powerful inhibitor of Abeta polymerization even at prolonged periods of incubation. Hence, the potential RAGE-Abeta structural interactions were further explored utilizing a series of computational chemistry algorithms. Our modeling suggests that a soluble dimeric RAGE assembly creates a positively charged well into which the negative charges of the N-terminal domain of dimeric Abeta dock.

Alzheimer Disease↗

PubMed2005

Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease.

Extracellular fibrillar amyloid deposits are prominent and universal Alzheimer's disease (AD) features, but senile plaque abundance does not always correlate directly with the degree of dementia exhibited by AD patients. The mechanism(s) and dynamics of Abeta fibril genesis and deposition remain obscure. Enhanced Abeta synthesis rates coupled with decreased degradative enzyme production and accumulating physical modifications that dampen proteolysis may all enhance amyloid deposit formation. Amyloid accumulation may indirectly exert the greatest pathologic effect on the brain vasculature by destroying smooth muscle cells and creating a cascade of negative impacts on cerebral blood flow. The most visible manifestation of amyloid dis-equilibrium could actually be a defense mechanism employed to avoid serious vascular wall degradation while the major toxic effects to the gray and white matter neurons are mediated by soluble oligomeric Abeta peptides with high beta-sheet content. The recognition that dynamic soluble oligomeric Abeta pools exist in AD and are correlated to disease severity led to neurotoxicity and physical conformation studies. It is now recognized that the most basic soluble Abeta peptides are stable dimers with hydrophobic regions sequestered from the aqueous environment and are capable of higher order aggregations. Time course experiments employing a modified ELISA method able to detect Abeta oligomers revealed dynamic intermolecular interactions and additional experiments physically confirmed the presence of stable amyloid multimers. Amyloid peptides that are rich in beta-sheet structure are capable of creating toxic membrane ion channels and a capacity to self-assemble as annular structures was confirmed in vitro using atomic force microscopy. Biochemical studies have established that soluble Abeta peptides perturb metabolic processes, provoke release of deleterious reactive compounds, reduce blood flow, induce mitochondrial apoptotic toxicity and inhibit angiogenesis. While there is no question that gross amyloid deposition does contribute to AD pathology, the destructive potential now associated with soluble Abeta suggests that treatment strategies that target these molecules may be efficacious in preventing some of the devastating effects of AD.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2004

Atherosclerosis of cerebral arteries in Alzheimer disease.

A growing body of evidence suggests that vascular disease underlies Alzheimer dementia. Atherosclerotic lesions in the circle of Willis and large leptomeningeal vessels were quantified and found to correlate with Alzheimer disease (AD) clinical diagnosis and neuropathology. We hypothesize that AD pathology is the complex end result of slowly evolving vascular disease and parenchymal lesions. Confirmation of a central role for vascular pathology in AD will suggest important treatment options and directions for additional interventions to stave off this dementia.

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PubMed2004

Atherosclerosis, vascular amyloidosis and brain hypoperfusion in the pathogenesis of sporadic Alzheimer's disease.

We postulate that severe atherosclerotic occlusion of the circle of Willis and leptomeningeal arteries is an important factor in the pathogenesis of some sporadic Alzheimer's disease (AD) cases. These arterial stenoses are complicated by an overwhelming amyloid accumulation in the walls of leptomeningeal and cortical arteries resulting in a significant decrease in perfusion pressure and consequent ischemia/hypoxia of the brain tissue. We also propose that the distal areas of the white matter (WM) will be the first affected by a lack of oxygen and nutrients. Our hypotheses are supported by the following observations: (1) the number of stenoses is more frequent in AD than in the control population (p = 0.008); (2) the average index of occlusion is greater in AD than in the control group (p < 0.00001); (3) the index of stenosis and the total number of stenoses per case are positively correlated (R = 0.67); (4) the index of stenosis correlates with the neuropathological lesions of AD and with the MMSE psychometric test; (5) the number and degree of atherosclerosis of the anterior, middle and posterior cerebral arteries is more severe in cases of AD than in the control population; (6) atherosclerosis severity is apparently associated with the severity of the vascular amyloidosis; (7) the WM rarefaction correlates with the severity of the atherosclerosis and vascular amyloidosis; (8) the total cell count and microvessel count in the areas of WM rarefaction correlate with the neuropathological lesions of AD and with the MMSE score. Our data strongly suggest that severe hemodynamic disturbances contribute to sporadic AD and support the numerous observations indicating cardiovascular system participation in the pathogenesis of these dementias.

Alzheimer Disease↗

PubMed2003

The human amyloid-beta precursor protein770 mutation V717F generates peptides longer than amyloid-beta-(40-42) and flocculent amyloid aggregates.

One of the familial forms of Alzheimer's disease (AD) encodes the amyloid-beta precursor protein (AbetaPP) substitution mutation V717F. This mutation is relevant to AD research, since it has been utilized to generate transgenic mice models to study AD pathology and therapeutic interventions. Amyloid beta (Abeta) peptides were obtained from the cerebral tissue of three familial AD subjects carrying the AbetaPP V717F mutation. A combination of ultracentrifugation, size-exclusion, and reverse-phase high performance liquid chromatography, tryptic and cyanogen bromide hydrolysis, amino acid analysis, and matrix-assisted laser desorption ionization and surface-enhanced laser desorption ionization mass spectrometry was used to characterize the familial AD mutant Abeta peptides. The AbetaPP V717F mutation, located 4-6 residues beyond the wild-type AbetaPP gamma-secretase cleavage site, yielded longer Abeta peptides with C termini between residues 43 and 54. In the cerebral cortex these peptides aggregated into thin water- and SDS-insoluble amyloid bundles that condensed into flocculent spherical plaques. In the leptomeningeal arteries the amyloid was deposited in moderate amounts and was primarily composed of the shorter and more soluble Abeta species ending at residues 40, 42, and 44. The single V717F mutation in AbetaPP results in distinctive and drastic changes in the length and tertiary structure of Abeta peptides, which appear to be responsible for the earlier clinical manifestations of dementia and death of these patients.

Amino Acids↗

PubMed2003

Circle of willis atherosclerosis is a risk factor for sporadic Alzheimer's disease.

OBJECTIVE: We conducted a quantitative investigation of brain arterial atherosclerotic damage and its relationship to sporadic Alzheimer's disease (AD). METHODS AND RESULTS: Fifty-four consecutive autopsy cases, 32 AD and 22 nondemented control subjects, were examined to establish the degree of arterial stenosis. Vessel external and lumenal area measurements were taken from 3-mm arterial cross-sections to calculate a stenosis index. AD patient circle of Willis arteries possessed a significant degree of stenosis as a consequence of multiple and severe atherosclerotic lesions. These lesions were significantly more severe in AD cases than in age-matched controls (P<0.0001), and the number of stenoses and the index of occlusion (R=0.67; P<0.00001) were positively correlated. In addition, the index of stenosis significantly correlated with the following measures of AD neuropathological lesions: total plaque score, neuritic plaque score, neurofibrillary tangle score, Braak stage score, and white matter rarefaction score. CONCLUSIONS: Our study reveals an association between severe circle of Willis atherosclerosis and sporadic AD that should be considered a risk factor for this dementia. These observations strongly suggest that atherosclerosis-induced brain hypoperfusion contributes to the clinical and pathological manifestations of AD.

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PubMed2003

A beta, aging, and Alzheimer's disease: a tale, models, and hypotheses.

In this paper we explore the potential functional role of the A beta peptides in the context of Alzheimer's disease (AD). We begin by defining the morphology of the amyloid deposits in relation to surrounding glial cells and, more importantly, in relation to the brain vasculature. Amyloid accumulation in the brain's microvasculature causes disturbances in the blood-brain barrier (BBB), and in larger arteries, impairment in control of regional cerebral blood flow due to myocyte degeneration. We postulate that the deposition of vascular amyloid may represent a hydrophobic protein plaster to seal leaks in the BBB, occasionally observed in aging and catastrophically common in AD. The vasoconstrictive activity of A beta may also be related to leaky vessels whereby decreasing the arterial diameter may also help to control breaches in the BBB. The admission of plasma neurotoxic proteins into the brain may be controlled by activation of microglia elicited by soluble A beta peptides creating a subtle, but permanent brain inflammatory reaction. We also delve into the influence that cholesterol metabolism may have in membrane topology and A beta production, and the close correlations that exist between cardiovascular disease and AD. Finally, we speculate about the possibility of a peripheral source of A beta that may, by crossing the BBB, contribute to the vascular and parenchymal deposits of A beta in the AD brain.

Aging↗

PubMedDate not supplied

Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by neurofibrillary tangles and by the accumulation of beta-amyloid (Abeta) peptides in senile plaques and in the walls of cortical and leptomeningeal arteries as cerebral amyloid angiopathy (CAA). There also is a significant increase of interstitial fluid (ISF) in cerebral white matter (WM), the pathological basis of which is largely unknown. We hypothesized that the accumulation of ISF in dilated periarterial spaces of the WM in AD correlates with the severity of CAA, with the total Abeta load in the cortex and with Apo E genotype. A total of 24 AD brains and 17 nondemented age-matched control brains were examined. CAA was seen in vessels isolated from brain by using EDTA-SDS lysis stained by Thioflavin-S. Total Abeta in gray matter and WM was quantified by immunoassay, ApoE genotyping by PCR, and dilatation of perivascular spaces in the WM was assessed by quantitative histology. The study showed that the frequency and severity of dilatation of perivascular spaces in the WM in AD were significantly greater than in controls (P< 0.001) and correlated with Abeta load in the cortex, with the severity of CAA, and with ApoE epsilon4 genotype. The results of this study suggest that dilation of perivascular spaces and failure of drainage of ISF from the WM in AD may be associated with the deposition of Abeta in the perivascular fluid drainage pathways of cortical and leptomeningeal arteries. This failure of fluid drainage has implications for therapeutic strategies to treat Alzheimer's disease.

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