Cerebral Amyloid Angiopathy: Accumulation of Aβ in Interstitial Fluid Drainage Pathways in Alzheimer's Disease

Weller, Roy O.; Massey, Adrian; Kuo, Yu Min; Roher, Alex E.

doi:10.1111/j.1749-6632.2000.tb06356.x

Cited by 255 publications

(308 citation statements)

References 20 publications

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“…***p Ͻ 0.001 versus all other groups, ANOVA, Tukey-Kramer post test. these particles is likely to change (Weller et al, 1998;Deane et al, 2008). Just as the presence of apoE is required for the formation of fibrillar amyloid, the lipidation status of apoE is also critical for amyloid formation, since poorly lipidated apoE results in more thioflavine S A␤ deposits (Bales et al, 1997;Wahrle et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

Bales¹,

Liu²,

Wu³

et al. 2009

J. Neurosci.

250

202

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To investigate the role of human apolipoprotein E (apoE) on A␤ deposition in vivo, we crossed PDAPP mice lacking mouse Apoe to targeted replacement mice expressing human apoE (PDAPP/TRE2, PDAPP/TRE3, or PDAPP/TRE4). We then measured the levels of apoE protein and A␤ peptides in plasma, CSF, and brain homogenates in these mice at different ages. We also quantified the amount of brain A␤ and amyloid burden in 18-month-old mice. In young PDAPP/TRE4 mice that were analyzed at an age before brain A␤ deposition, we observed a significant decrease in the levels of apoE in CSF and brain when compared with age-matched mice expressing either human E2 or E3. The brain levels of A␤42 in PDAPP/TRE4 mice were substantially elevated even at this very early time point. In older PDAPP/TRE4 mice, the levels of insoluble apoE protein increased in parallel to the dramatic rise in brain A␤ burden, and the majority of apoE was associated with A␤. In TRE4 only mice, we also observed a significant decrease in the level of apoE in brain homogenates. Since the relative level of apoE mRNA was equivalent in PDAPP/TRE and TRE only mice, it appears that post-translational mechanisms influence the levels of apoE protein in brain (E4 Ͻ E3 Ͻ Ͻ E2), resulting in early and dramatic apoE isoform-dependent effects on brain A␤ levels (E4 Ͼ Ͼ E3 Ͼ E2) that increase with age. Therapeutic strategies aimed at increasing the soluble levels of apoE protein, regardless of isoform, may effectively prevent and (or) treat Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

Bales¹,

Liu²,

Wu³

et al. 2009

J. Neurosci.

250

202

View full text Add to dashboard Cite

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“…22 A␤ peptides may be produced primarily within neurons; after being secreted into the interstitial space, the interstitial fluids flow into the perivascular space of local arterioles and are then transported opposite to the direction of the blood into larger arteries, where the A␤ is ultimately drained from the brain. 48 Interestingly, the M 1 R agonist AF267B decreased vascular (eg, capillaries and arterioles) and perivascular A␤ 42 deposits in the cortex and cerebrospinal fluid of rabbits lesioned by the cholinotoxin M20.4-saporin injected into the nucleus basalis. 16 Herein, we gained further insights into the mechanisms that drive the A␤ deposition in the cerebrovasculature, showing that stimulation of amyloidogenic APP processing in the Tg-SwDI-M 1 R Ϫ/Ϫ mice culminates within increased A␤ deposits in the cerebrovasculature.…”

Section: Discussionmentioning

confidence: 99%

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

Medeiros

Kitazawa

Caccamo

et al. 2011

The American Journal of Pathology

106

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Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and ␤-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M 1 receptors (M 1 Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M 1 Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M 1 R ؊/؊ mice. Our data show that M 1 R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M 1 R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar A␤ in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M 1 R were attributed to changes in the glycogen synthase kinase 3␤ and protein kinase C activities. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive impairment and dementia. The neuropathological hallmarks of AD are amyloid plaques, composed of ␤-amyloid (A␤) peptides, and neurofibrillary tangles, composed of the hyperphosphorylated tau protein. The deposition of fibrillar A␤ in the cerebrovasculature, a condition known as cerebral amyloid angiopathy (CAA), is also a prominent feature of AD. Together with associated processes, such as inflammation and oxidative stress, these pathological cascades contribute to loss of synaptic integrity and progressive neurodegeneration. 1Restoring cholinergic dysfunction has been a primary means of improving the cognitive decline in AD because four of the five Food and Drug Administration-approved drugs are acetylcholinesterase inhibitors, with the notable exception of memantine.2 Acetylcholinesterase inhibitors provide mild symptomatic relief but eventually lose efficacy over time, most likely because they are not disease-modifying agents.1 Alternatively, recent evidence 3,4 indicates that stimulation of muscarinic acetylcholine receptors, in particular the M 1 receptor (M 1 R), restores cognition and attenuates AD-like pathological features in several different animal models, rendering it an attractive therapeutic approach for AD. The M 1 R is the most abundant muscarinic acetylcholine receptor subtype in the cerebral cortex and hippocampus, the two main brain reSupported by grants from the NIH (NIH/NIAMS K99AR054695 to M.K.; NIH/NIA R01AG20335 and Program Project AG00538 to F.M.L.).

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“…These findings show that Ab in CSF also has access to vascular clearance, either through uptake and degradation by vascular mural cells 122,123 or by efflux across the BBB after entry into ISF. 52 Conversely, sluggish bulk flow of CSF/ISF may cause Ab accumulation in the perivascular spaces, 124 and contribute to vascular toxicity in AD. This may also be important to cerebral amyloid angiopathy (CAA) that is observed in a majority of pathologically diagnosed AD cases.…”

Section: Cerebrospinal Fluid/interstitial Fluid Bulk Flow Brain Barrmentioning

confidence: 99%

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Erickson

Banks

2013

J Cereb Blood Flow Metab

458

363

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The blood-brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-b (Ab) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Ab pathology. Keywords: Alzheimer's disease; blood-brain barrier; cerebrospinal fluid; diabetes; inflammation; neurovascular unit INTRODUCTION Alzheimer's disease (AD) is the most common type of dementia, and affects B36 million individuals worldwide (http://www.alz. co.uk/research/world-report). The majority of individuals afflicted with AD initially present with symptoms of memory loss and cognitive impairment late in life (Z65 years old). These symptoms increase in severity as AD progresses, often become so debilitating that institutionalization is necessary, and are eventually fatal. Therefore, AD is a disease with tremendous socioeconomic cost. Because of the growing aged population and lack of treatments that can prevent or slow disease progression, future AD prevalence is expected to increase to an extent that it may threaten the sustainability of healthcare systems worldwide. This necessitates a global effort to better understand AD, with the goal of developing treatments that can prevent or slow AD progression. Journal of Cerebral BloodMuch of the focus in AD research has been on amyloid-b peptide (Ab) and tau, which are the protein constituents of the hallmark senile plaques and neurofibrillary tangles that pathologically define AD. The amyloid cascade hypothesis, initially proposed by Hardy and Higgins in 1992, 1 updated by Hardy and Selkoe in 2002, 2 and still a prevalent focus of AD research today, states that deposition of Ab in the brain is the initiating event in AD. Although the hypothesis remains generally accepted, it is also increasingly evident that Ab plays a complex, multifaceted role in AD progression. In rare, familial forms of AD, mutations in the Ab precursor protein (APP) or in presenilin proteins, the enzymes that cleave Ab from APP, cause increased Ab deposition. In the remainder of AD cases, it is thought that Ab deposition results from deficient clearance. 2 Multiple routes of clearance have been elucidat...

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Cerebral Amyloid Angiopathy: Accumulation of Aβ in Interstitial Fluid Drainage Pathways in Alzheimer's Disease

Cited by 255 publications

References 20 publications

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

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