Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade (original) (raw)
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Cerebrovascular Pathology and Amyloid Plaque Formation in Alzheimer’s Disease
Current Alzheimer Research, 2014
Accumulation, aggregation and deposition of the amyloid-(A) peptides in the brain are widely accepted as the central events in the pathogenesis of Alzheimer's disease (AD). Any factor that is capable of causing these events is potentially a risk factor for AD. In the last decade, evidence has accumulated to support the association between cerebral vascular diseases (CVD) and AD. CVD is known to induce amyloid deposition and affects the age of onset for sporadic AD; whereas, amyloid deposition has been shown to cause cerebrovascular degeneration. In this review, we propose a positive feedback loop between CVD and amyloid deposition. The disease cycle could be triggered by aging and/or other environmental factor-associated CVD, as in late-onset sporadic AD patients, or by over production of A , as in the familial AD patients and amyloid precursor protein transgenic animals.
Vascular abnormalities: the insidious pathogenesis of Alzheimer’s disease☆
Neurobiology of Aging, 2000
Alzheimer's disease (AD) and cerebrovascular dementia (CVD) are two major causes of senile dementia in elderly individuals. Mounting evidence from epidemiological, clinical, and neuropathological studies suggests that there is considerable overlap between AD and CVD with respect to risk factors, prevalence, and pathological changes. Although our lack of understanding on the important contribution of vascular disturbance to pathogenesis of AD has further hindered our understanding of AD, data on the roles of cerebrovascular diseases and systemic vascular diseases in AD need to be carefully analyzed to avoid misinterpretation. Here, we review studies on the cerebral vasculature, cardiac vasculature, and apoE that lead us to contend that vascular abnormalities are likely an important mechanism underlying dementia. Because early and aggressive intervention is available to prevent and treat a number of vascular diseases, therapies that attenuate vascular risk factors could be valuable in preventing and treating AD.
International Journal of Molecular Sciences, 2021
Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a d...
Vascular pathology: Cause or effect in Alzheimer disease?
Neurología (English Edition), 2017
Abstract Introduction Alzheimer disease (AD) is the main cortical neurodegenerative disease. The incidence of this disease increases with age, causing significant medical, social and economic problems, especially in countries with ageing populations. Objective This review aims to highlight existing evidence of how vascular dysfunction may contribute to cognitive impairment in AD, as well as the therapeutic possibilities that might arise from this evidence. Development The vascular hypothesis emerged as an alternative to the amyloid cascade hypothesis as an explanation for the pathophysiology of AD. This hypothesis locates blood vessels as the origin for a variety of pathogenic pathways that lead to neuronal damage and dementia. Destruction of the organisation of the blood–brain barrier, decreased cerebral blood flow, and the establishment of an inflammatory context would thus be responsible for any subsequent neuronal damage since these factors promote aggregation of β-amyloid peptide in the brain. The link between neurodegeneration and vascular dysfunction pathways has provided new drug targets and therapeutic approaches that will add to the treatments for AD. Conclusions It is difficult to determine whether the vascular component in AD is the cause or the effect of the disease, but there is no doubt that vascular pathology has an important relationship with AD. Vascular dysfunction is likely to act synergistically with neurodegenerative changes in a cycle that exacerbates the cognitive impairment found in AD.
Cerebral amyloid angiopathy and Alzheimer’s disease
Neurobiology of Aging, 2004
Cerebral amyloid angiopathy (CAA) is increasingly recognized as a major contributor of Alzheimer's disease (AD) pathogenesis. To date, vascular deposits and not parenchymal plaques appear more sensitive predictors of dementia. Amyloid deposition in and around cerebral blood vessels plays a central role in a series of response mechanisms that lead to changes in the integrity of the blood-brain barrier, extravasations of plasma proteins, edema formation, release of inflammatory mediators and matrix metalloproteases which, in turn, produce partial degradation of the basal lamina with the potential to develop hemorrhagic complications. The progressive buildup of amyloid deposits in and around blood vessels chronically limits blood supply and causes focal deprivation of oxygen, triggering a secondary cascade of metabolic events several of which involve the generation of nitrogen and oxygen free radicals with consequent oxidative stress and cell toxicity. Many aspects of CAA in early-and late-onset AD-the special preference of Aβ40 to deposit in the vessel walls, the favored vascular compromise associated with many Aβ genetic variants, the puzzling observation that some of these vasculotropic variants solely manifest with recurrent hemorrhagic episodes while others are mainly associated with dementia-await clarification. Non-Aβ cerebral amyloidoses reinforce the viewpoint that plaque burden is not indicative of dementia while highlighting the relevance of nonfibrillar lesions and vascular involvement in the disease pathogenesis. The lessons learned from the comparative study of Aβ and non-Aβ cerebral amyloidosis provide new avenues and alternative models to study the role of amyloid in the molecular basis of neurodegeneration. Alzheimer's disease (AD) is the most common form of dementia in humans over the age of 65, affecting more than 50% of individuals 85 or older. It is a debilitating neurodegenerative disorder that affects millions of people constituting one of the major Public Health concerns in all developed countries. Neuropathological hallmarks of AD are the presence of intraneuronal neurofibrillary tangles (NFT)-deposits of hyperphosphorylated protein tau in the form of paired helical filaments-together with the existence of parenchymal extracellular deposits composed of both diffuse pre-amyloid lesions and mature amyloid plaques. Although its significance was ignored for decades, together with these lesions, fibrillar amyloid deposition is also commonly observed in medium-sized and small cerebral vessels,
Medical Research Archives
Historically, cerebrovascular abnormalities were recognized as prominent in the pathology of age-related dementia. In more recent decades, however, research and funding for development of therapeutics has almost entirely been focused on ß-amyloid and tau deposits (as described by Alzheimer in pre-senile dementia), despite a lack of conclusive evidence of a causal relationship or efficacy of targeted treatment on cognitive decline or dementia. Here we present a brief history of the evidence for a dominant vascular component of Alzheimer’s Disease and highlight a potential target for slowing the functional progression of the disease.
Vascular factors in Alzheimer's disease: Alzheimer research forum live discussion
Journal of Alzheimer's Disease, 2005
June Kinoshita: Welcome, everyone. I am moderating today's chat. I would like to ask David and Julie to recap the question they addressed in their study. David Bennett: We examined the extent to which cerebral infarcts and Alzheimer's disease (AD) pathology were additive to risk of dementia, or interactivemeaning the two increased risk more than the sum-or both [1]. Julie Schneider: In other words, are they additive or multiplicative? June Kinoshita: And you found that they were additive, correct? David Bennett: We found an additive effect, meaning infarcts and AD pathology each made a unique, and relatively independent, contribution to dementia. 1 Note: The transcript has been edited for clarity and accuracy. Craig Atwood: Which pathology are we talking about, amyloid and infarct number and size? Julie Schneider: We looked at number, volume, as well as location, and the findings were the same. David Bennett: AD pathology was standard silver stained counts of neuritic plaques (NP), diffuse plaques (DP), and neurofibrillary tangles (NFT). Gjumrakch Aliev: I do not think that these two pathologies can be separated. This is one process. Craig Atwood: I agree with Gjumrakch. Gjumrakch Aliev: We need to look back before any amyloid or any stroke conditions have appeared. David Bennett: I am not sure I get Gjumrakch's point.
Cerebrovascular endothelial dysfunction mediated by β-amyloid
NeuroReport, 1997
Alzheimer's disease (AD) is characterized by progressive dementia in the elderly and is accompanied by accumulation of b-amyloid protein (A) in the brain. The pathogenesis of AD remains unknown, but A toxicity is believed to be the major cause of neurodegeneration. In this study we demonstrate that A causes damage to the endothelial cells in cerebral arteries. The endothelial dysfunction was evidenced by altered physiological activity and morphological changes. The endothelial damage was prevented by antioxidants indicating the production of toxic oxygen radicals by A. Our study provides a link between the free radical theory of aging and the amyloid theory of AD. Protection of blood vessels from the toxic effects of A may offer new approaches to AD treatment. In addition to AD, A may contribute to the pathology of vascular disorders associated with aging such as hypertension, coronary artery disease, ischemia, and stroke.