Brain Clearance of Alzheimer's Amyloid-β40 in the Squirrel Monkey: A SPECT Study in a Primate Model of Cerebral Amyloid Angiopathy

Bading, James R.; Yamada, Shinya; Mačkić, Jasmina B.; Kirkman, Linda; Miller, Carol A.; Calero, Miguel; Ghiso, Jorge; Frangione, Blas; Zloković, Berislav V.

doi:10.1080/10611860290031831

Cited by 85 publications

(42 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The participation of LRP-1 in BBB efflux of Ab is supported by the finding that knockdown of LRP-1 in the BBB using antisense oligonucleotides causes impaired Ab efflux, accumulation of Ab in the brains of young, wild-type mice, and cognitive impairments. 54 The association of impaired Ab efflux with AD was substantiated by observations of decreased Ab efflux in rodent models of AD 55,56 as well as in aged squirrel monkeys 57 and in a small sample set of humans with AD. 58 More recently, it has become evident that other transporters in the BBB facilitating Ab efflux also become impaired in AD.…”

Section: Defects In Blood-brain Barrier Transporters That May Contribmentioning

confidence: 96%

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

Erickson

Banks

2013

J Cereb Blood Flow Metab

476

363

View full text Add to dashboard Cite

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...

show abstract

Section: Defects In Blood-brain Barrier Transporters That May Contribmentioning

confidence: 96%

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

Erickson

Banks

2013

J Cereb Blood Flow Metab

476

363

View full text Add to dashboard Cite

show abstract

“…Several studies have indicated that LRP expression in brain endothelium decreases with normal aging in rodents, nonhuman primates, and humans, as well as in AD models and AD patients (Kang et al 2000;Shibata et al 2000;Bading et al 2002;Deane et al 2004;Donahue et al 2006;Bell and Zlokovic 2009). LRP reductions have been reported in cerebral VSMCs associated with Ab accumulation in the wall of small pial and intracerebral arteries ).…”

Section: Lrpmentioning

confidence: 99%

Neurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease

Sagare

Bell

Zloković

2012

Cold Spring Harbor Perspectives in Medicine

215

177

View full text Add to dashboard Cite

Neurovascular dysfunction is an integral part of Alzheimer disease (AD). Changes in the brain vascular system may contribute in a significant way to the onset and progression of cognitive decline and the development of a chronic neurodegenerative process associated with accumulation of amyloid b-peptide (Ab) in brain and cerebral vessels in AD individuals and AD animal models. Here, we review the role of the neurovascular unit and molecular mechanisms in cerebral vascular cells behind the pathogenesis of AD. In particular, we focus on blood-brain barrier (BBB) dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Ab from brain. The data reviewed here support an essential role of the neurovascular and BBB mechanisms in AD pathogenesis.

show abstract

“…Yet, the rate of A␤ production and ␤-secretase activity seems to remain constant throughout the life span of these mice (14). A defect in reverse transport to the systemic circulation as shown for the A␤ Dutch variant (50,51) together with inefficient local proteolysis may determine a rise in the levels of A␤ in the brain and therefore accelerate its rate of aggregation and deposition (16,29,52). In the case of human diseases associated with mutations clustered within the middle portion of A␤, such accumulation shows a remarkable predisposition for vessels in which A␤ oligomers may be toxic to endothelial and smooth muscle cells.…”

Section: Expression and Characterization Of Recombinant Rat Ide-mentioning

confidence: 99%

Differential Degradation of Amyloid β Genetic Variants Associated with Hereditary Dementia or Stroke by Insulin-degrading Enzyme

Morelli

Llovera

González

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Inherited amino acid substitutions at position 21, 22, or 23 of amyloid ␤ (A␤) lead to presenile dementia or stroke. Insulin-degrading enzyme (IDE) can hydrolyze A␤ wild type, yet whether IDE is capable of degrading A␤ bearing pathogenic substitutions is not known. We studied the degradation of all of the published A␤ genetic variants by recombinant rat IDE (rIDE). Monomeric A␤ wild type, Flemish (A21G), Italian (E22K), and Iowa (D23N) variants were readily degraded by rIDE with a similar efficiency. However, proteolysis of A␤ Dutch (E22Q) and Arctic (E22G) was significantly lower as compared with A␤ wild type and the rest of the mutant peptides. In the case of A␤ Dutch, inefficient proteolysis was related to a high content of ␤ structure as assessed by circular dichroism. All of the A␤ variants were cleaved at Glu 3 -Phe 4 and Phe 4 -Arg 5 in addition to the previously described major sites within positions 13-15 and 18 -21. SDS-stable A␤ dimers were highly resistant to proteolysis by rIDE regardless of the variant, suggesting that IDE recognizes a conformation that is available for interaction only in monomeric A␤. These results raise the possibility that upregulation of IDE may promote the clearance of soluble A␤ in hereditary forms of A␤ diseases.The accumulation of amyloid ␤ peptide (A␤) 1 in the brain is a central process in a number of human neurodegenerative disorders that may be grouped as "amyloid ␤ diseases" (1). In Alzheimer's disease, A␤ is mainly found within senile plaques in the neurophil and vascular lesions, whereas in sporadic and hereditary amyloid angiopathies, A␤ deposits are mainly associated with cortical and leptomeningeal vessels leading to stroke or multi-infarct dementia. To a lesser extent, cerebral A␤ deposits are also present in normal aging (2). Autosomal dominant mutations in the amyloid ␤ precursor protein (A␤ PP) gene result in amino acid substitutions at position 21, 22, or 23 of A␤ sequence. Although these A␤ variants present with a primarily vascular deposition, they translate into different clinical phenotypes. In this regard, A␤ Arctic (E22G) and A␤ Iowa (D23N) are characterized by presenile dementia and A␤ Flemish (A21G) is associated with early onset dementia and cerebral hemorrhage, whereas A␤ Dutch (E22Q) and A␤ Italian (E22K) variants have a predominant vascular phenotype characterized by massive strokes (3-7). The underlying mechanism of aggregation and deposition in vivo may be strongly influenced by the type of amino acid substitution as well as the location of mutations in the A␤ peptide. In vitro studies have shown that A␤ E22Q and A␤ D23N form typical amyloid fibrils at a higher rate than wild-type A␤ and that A␤ E22G assembles into unique protofibrils that may be toxic to neurons (3, 8 -10). In the case of A␤ A21G, overproduction of the peptide may contribute as a pathogenic mechanism (11, 12). Regarding A␤ E22K, deposition seems not to be related with fibril formation rate, and yet this variant may be toxic to human cerebrovascular smooth muscle cells in cult...

show abstract

Brain Clearance of Alzheimer's Amyloid-β40 in the Squirrel Monkey: A SPECT Study in a Primate Model of Cerebral Amyloid Angiopathy

Cited by 85 publications

References 32 publications

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

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

Neurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease

Differential Degradation of Amyloid β Genetic Variants Associated with Hereditary Dementia or Stroke by Insulin-degrading Enzyme

Contact Info

Product

Resources

About