Biochemistry of Amyloid  -Protein and Amyloid Deposits in Alzheimer Disease

Masters, Colin L.; Selkoe, Dennis J.

doi:10.1101/cshperspect.a006262

Cited by 485 publications

(423 citation statements)

References 228 publications

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“…This observation reveals a unique role for CD36 in vascular Aβ1-40 accumulation and amyloid deposition. Given that the effect of CD36 is restricted to Aβ1-40, it is unlikely that the attenuation is related to reduced Aβ cleavage from APP by secretases, because in that case reductions in both Aβ1-40 and Aβ1-42 would be anticipated (37). Rather, the selectivity of the reduction in Aβ1-40 points to an enhanced clearance or catabolism of the peptide.…”

Section: Discussionmentioning

confidence: 99%

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Park

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

133

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Deposition of amyloid-β (Aβ) in cerebral arteries, known as cerebral amyloid angiopathy (CAA), occurs both in the setting of Alzheimer's disease and independent of it, and can cause cerebrovascular insufficiency and cognitive deficits. The mechanisms leading to CAA have not been established, and no therapeutic targets have been identified. We investigated the role of CD36, an innate immunity receptor involved in Aβ trafficking, in the neurovascular dysfunction, cognitive deficits, and amyloid accumulation that occurs in mice expressing the Swedish mutation of the amyloid precursor protein (Tg2576). We found that Tg2576 mice lacking CD36 have a selective reduction in Aβ1-40 and CAA. This reduced vascular amyloid deposition was associated with preservation of the Aβ vascular clearance receptor LRP-1, and protection from the deleterious effects of Aβ on cerebral arterioles. These beneficial vascular effects were reflected by marked improvements in neurovascular regulation and cognitive performance. Our data suggest that CD36 promotes vascular amyloid deposition and the resulting cerebrovascular damage, leading to neurovascular dysfunction and cognitive deficits. These findings identify a previously unrecognized role of CD36 in the mechanisms of vascular amyloid deposition, and suggest that this scavenger receptor is a putative therapeutic target for CAA and related conditions. T here is increasing evidence that alterations in the structure and function of cerebral blood vessels contribute to the brain dysfunction underlying Alzheimer's disease (AD) (1, 2). Whereas resting cerebral blood flow (CBF) is reduced early in course of AD (3, 4), the increase in CBF induced by brain activity (functional hyperemia), a vital mechanism matching the metabolic demands of active neurons with the delivery of nutrients through blood flow, is suppressed (5, 6). With disease progression, deposition of amyloid-β (Aβ) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), damages cerebrovascular cells, weakens vessel walls, and disrupts vascular function further (7). CAA also occurs independent of AD and has emerged as a frequent cause of brain hemorrhage, silent infarct, and cognitive impairment (8, 9).Studies in mice overexpressing mutated forms of the amyloid precursor protein (APP) have demonstrated that Aβ peptides, especially Aβ1-40, which accumulates preferentially in cerebral blood vessels, alter cerebrovascular function, resulting in vasoconstriction, impaired functional hyperemia, and inability of the endothelium to regulate vascular tone (10-12).These studies have raised the possibility that Aβ, in addition to damaging neurons and glia, also threatens the cerebral blood supply and increases the brain's susceptibility to hypoxia-ischemia (1, 13). Furthermore, considering that vascular transport is a key pathway for clearance of Aβ from the brain (14), these vascular alterations also may enhance the accumulation of Aβ in brain and cerebral blood vessels.Converging evidence indicates that Aβ exerts i...

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Section: Discussionmentioning

confidence: 99%

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Park

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

133

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“…Amyloid-␤ (A␤) is a core component of the plaque or lesion found in the neocortex and hippocampus of brains affected by Alzheimer's disease [117,125,126]. It is formed after sequential proteolytic cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein.…”

Section: Amyloid-β Factors and Alzheimer's Diseasementioning

confidence: 99%

Wine consumption, cognitive function and dementias – A relationship?

Stockley

2016

NUA

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Abstract. Healthy cognitive function is essential for quality of life, wellbeing and independent living, and is negatively associated with dementias. A series of longitudinal and neuro-imaging studies in the elderly have shown that light to moderate wine consumption is neuro-protective although heavy or abusive alcohol consumption is neuro-toxic. A J-shaped relationship between alcohol consumption, cognitive dysfunction and risk of dementias is also observed for younger and middle aged consumers. There is also no data to suggest that long-term light to moderate alcohol consumption exacerbates age-related cognitive decline and impairment. An optimal amount of wine for neuro-protection appears to be up to 30 g alcohol daily.There are multiple plausible biological mechanisms in various animal models, in vitro and in vivo for wine-derived phenolic compounds which go beyond their antioxidant activity and attenuation of oxidative stress.

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“…2,7,15 Cognitive decline in human subjects appears to depend more on the length (Ab 1-42 vs shorter forms) and postproduction alterations of Ab (formation of dimers/oligomers) than simply the total amount produced. 16 SDS-stable dimers are a major form of soluble Ab extracted from most AD brains and may be the essential building block of the most synaptotoxic Ab species that can induce dendritic spine loss and AD progression. 16,17 Synapse loss can be detected in amyloid precursor protein (APP) swe /presenilin 1 (PS1)DE9 mice by staining for synaptic marker proteins, and the loss of synaptic markers is dependent on the presence of PrP C .…”

Section: Prpmentioning

confidence: 99%

“…16 SDS-stable dimers are a major form of soluble Ab extracted from most AD brains and may be the essential building block of the most synaptotoxic Ab species that can induce dendritic spine loss and AD progression. 16,17 Synapse loss can be detected in amyloid precursor protein (APP) swe /presenilin 1 (PS1)DE9 mice by staining for synaptic marker proteins, and the loss of synaptic markers is dependent on the presence of PrP C . 7 Treatment of aged APP swe / PS1DE9 mice with anti-PrP C antibodies allows a recovery of synaptic markers in the dentate gyrus of the hippocampus, a brain region associated with learning and memory.…”

Section: Prpmentioning

confidence: 99%