Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides

Bali, Jitin; Gheinani, Ali Hashemi; Zurbriggen, Sebastian; Rajendran, Lawrence

doi:10.1073/pnas.1201632109

Cited by 90 publications

(76 citation statements)

References 37 publications

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“…This is in contrast to similar knockdown studies of various LOADrelated genes (e.g. BIN1, Clustrin, and CD33) where no effect on APP processing was observed, but ABCA7 was not examined in this particular investigation (37). In the current study, loss of ABCA7 in cells overexpressing APPSw resulted in increased ␤-cleavage products and A␤ secretion.…”

Section: Discussioncontrasting

confidence: 53%

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

Satoh

Abe-Dohmae

Yokoyama

et al. 2015

Journal of Biological Chemistry

108

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Background:The ATP-binding cassette transporter A7 (ABCA7) is a risk factor for sporadic Alzheimer disease (AD). Results: Loss of ABCA7 promoted A␤ processing and pathology in cell culture and AD mouse models. Conclusion: Altered ABCA7 function may contribute to AD by impacting A␤ production in addition to clearance. Significance: AD-related risk factors may contribute to disease progression through multiple pathways.The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-␤ (A␤). Suppression of endogenous ABCA7 in several different cell lines resulted in increased ␤-secretase cleavage and elevated A␤. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid A␤42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble A␤ as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble A␤ and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas A␤ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased A␤ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility.Genome-wide association studies have identified the ATPbinding cassette transporter A7 (ABCA7) 2 as a susceptibility locus for late onset Alzheimer disease (LOAD) (1, 2). The single nucleotide polymorphisms (SNPs) associated with LOAD are distributed in various domains of the ABCA7 gene and include intronic SNPs and a coding sequence causing G1527A substitution. Studies have identified loci in different clusters, suggesting multiple sites within the ABCA7 gene associated with increased risk for AD (3). However, there is no indication that individuals with at-risk alleles display any differences in ABCA7 expression.ABCA7 is a member of the ATP-binding cassette transporter family largely involved in lipid transport and homeostasis (4). Its highly homologous member ABCA1 has also been linked to LOAD through cholesterol and processing of the amyloid precursor protein (5-7). Overexpression of ABCA7 resulted in a significant decrease in amyloid-...

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Section: Discussioncontrasting

confidence: 53%

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

Satoh

Abe-Dohmae

Yokoyama

et al. 2015

Journal of Biological Chemistry

108

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“…It is conceivable that the increased accumulation of amyloid beta peptides in sporadic AD results from increased expression of APP gene and / or increased processing of the APP gene product in the amyloidogenic pathway by means of β and γ secretases and / or decreased catabolism and clearance of the peptides from the brain. In case of familial AD, the mutations in APP, PS1 or PS2 gene may lead to similar effects with accumulation of amyloid beta peptides in the brain, and the 'Amyloid Cascade Hypothesis' as the pathogenic mechanism of AD has gained huge support from identification of these familial AD mutation [29,31]. The other suggested mechanism in AD pathogenesis emphasizes the neuronal and synaptic dysfunctions caused by the abnormal accumulation of phosphorylated tau protein (tauopathy) [32,33].…”

Section: Pathogenesis Of Alzheimer's Diseasementioning

confidence: 99%

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Chakrabarti¹,

Khemka²,

Banerjee³

et al. 2015

Aging and disease

112

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Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, proinflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.

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“…Similarly, also CLU and PICALM had been shown to enhance the transport of Aβ across the blood-brain barrier and the bloodcerebrospinal fluid barrier [12] [13] [14] [15]. In line with the notion that LOAD genes do not specifically affect Aβ production, a recent study did not detect specific effects of the knockdowns of several LOAD susceptibility genes on Aβ levels or the 42:40 ratio in a HeLa cell APP overexpression system [1].…”

Section: Introductionmentioning

confidence: 54%

“…While genome-wide association studies (GWAS) have identified certain genetic risk factors associated with late-onset AD, the mechanisms through which they contribute to the pathogenesis are still elusive. Previously, using a HeLa cell model of Aβ production, it was shown that, in contrast to the early-onset AD causing mutations, knockdown of late-onset AD susceptibility genes did not specifically affect the Aβ 42 :Aβ 40 ratio [1]. To validate these findings in a neuronal setting without any overexpression of APP, here we re-addressed the role of six late-onset AD risk genes (APOE, BIN1, PICALM, CLU, PRNP and CST3) in the regulation of γ-secretase mediated APP processing in wild-type mouse primary neurons by analyzing Aβ x-40 and Aβ x-42 .…”

mentioning

confidence: 99%

Analysis of Aβ<sub>x-42</sub>/Aβ<sub>x-40</sub> and Tau upon siRNA-mediated downregulation of APOE, BIN1, PICALM, CLU, PRNP and CST3 in wildtype mouse primary neurons

Siegel

Rajendran

2018

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Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is a progressive neurodegenerative disorder that is characterized by the abundant presence of cerebral β-amyloid (Aβ) plaques and neurofibrillary Tau tangles. The rare, early-onset AD is caused by mutations mainly within either the amyloid precursor protein (APP) or Presenilins 1 or 2 (PS1 or PS2), the catalytic subunits of the γ-secretase complex. These mutations either increase overall Aβ production or specifically alter γ-secretase mediated processing towards an increased production ratio of Aβ 42 :Aβ 40 . For late-onset AD, however, which accounts for the vast majority of AD cases, the exact mechanisms by which the disease is caused are not known. While genome-wide association studies (GWAS) have identified certain genetic risk factors associated with late-onset AD, the mechanisms through which they contribute to the pathogenesis are still elusive. Previously, using a HeLa cell model of Aβ production, it was shown that, in contrast to the early-onset AD causing mutations, knockdown of late-onset AD susceptibility genes did not specifically affect the Aβ 42 :Aβ 40 ratio [1]. To validate these findings in a neuronal setting without any overexpression of APP, here we re-addressed the role of six late-onset AD risk genes (APOE, BIN1, PICALM, CLU, PRNP and CST3) in the regulation of γ-secretase mediated APP processing in wild-type mouse primary neurons by analyzing Aβ x-40 and Aβ x-42 . In addition, we extended the analysis by also including measurements of total Tau protein and phosphorylation of Tau at Threonine 231, a non-physiological phosphorylation site that is associated with AD. The siRNA-mediated knockdown of the studied LOAD risk genes neither affected the Aβ x-42 :Aβ x-40 ratio nor altered the levels of total Tau or phospho(Thr231)-Tau. Our results thus show that acute downregulation of these genes in wild-type mouse primary neurons does not significantly impact on γ-secretase mediated APP processing nor Tau homeostasis or Tau phosphorylation.

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Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides

Cited by 90 publications

References 37 publications

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Analysis of Aβ<sub>x-42</sub>/Aβ<sub>x-40</sub> and Tau upon siRNA-mediated downregulation of APOE, BIN1, PICALM, CLU, PRNP and CST3 in wildtype mouse primary neurons

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