1α,25-Dihydroxyvitamin D<sub>3</sub>Reduces Cerebral Amyloid-β Accumulation and Improves Cognition in Mouse Models of Alzheimer's Disease

Durk, Matthew R.; Han, Kyung Ho; Chow, Edwin; Ahrens, Rosemary; Henderson, Jeffrey T.; Fraser, Paul E.; Pang, K. Sandy

doi:10.1523/jneurosci.2711-13.2014

Cited by 134 publications

(106 citation statements)

References 51 publications

(35 reference statements)

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“…Slides were scanned using the Mirax Scan v.1.11 software and Zeiss Mirax Slide Scanner at 20ϫ magnification with a Zeiss 20ϫ/0.8 objective lens and a Marlin F146-C charge-coupled device camera. The rendered digital images were analyzed using the color deconvolution algorithm in the ImageScope software as described previously (31). RGB values were determined for both the applied hematoxylin and 3,3Ј-diaminobenzidine stains.…”

Section: Methodsmentioning

confidence: 99%

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

Satoh

Abe-Dohmae

Yokoyama

et al. 2015

Journal of Biological Chemistry

106

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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: Methodsmentioning

confidence: 99%

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

Satoh

Abe-Dohmae

Yokoyama

et al. 2015

Journal of Biological Chemistry

106

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“…Inhibiting or knocking out P-glycoprotein increases brain β-amyloid levels (Cirrito et al, 2005). Conversely, increasing P-glycoprotein expression with PXR or vitamin D receptor (VDR) ligands reduces brain β-amyloid content (Brenn et al, 2014;Durk et al, 2014;. These results suggest that one route for β-amyloid efflux from the brain could be through receptor-mediated endocytosis (LRP-1) at the abluminal plasma membrane of the brain capillary endothelium and efflux mediated by P-glycoprotein at the luminal plasma membrane.…”

Section: Diseasementioning

confidence: 99%

Regulation of ABC Transporters Blood–Brain Barrier

Miller

2015

Advances in Cancer Research

131

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“…Rodents fed with vitamin D 3 -enriched diets show a significant reduction of brain Aβ burden along with improved cognitive performances [76,77,78]. Inversely, we and others observed an increase of the Aβ40 and Aβ42 content in the brain tissue of vitamin D-deficient animals [78,79].…”

Section: Vitamin Dmentioning

confidence: 64%

The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease

Grimm

Mett

Hartmann

2016

IJMS

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Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing the microtubule-associated protein tau. Aβ peptides are derived from the sequential processing of the amyloid precursor protein (APP) by enzymes called secretases, which are strongly influenced by the lipid environment. Several vitamins have been reported to be reduced in the plasma/serum of AD-affected individuals indicating they have an impact on AD pathogenesis. In this review we focus on vitamin E and the other lipophilic vitamins A, D, and K, and summarize the current knowledge about their status in AD patients, their impact on cognitive functions and AD risk, as well as their influence on the molecular mechanisms of AD. The vitamins might affect the generation and clearance of Aβ both by direct effects and indirectly by altering the cellular lipid homeostasis. Additionally, vitamins A, D, E, and K are reported to influence further mechanisms discussed to be involved in AD pathogenesis, e.g., Aβ-aggregation, Aβ-induced neurotoxicity, oxidative stress, and inflammatory processes, as summarized in this article.

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1α,25-Dihydroxyvitamin D₃Reduces Cerebral Amyloid-β Accumulation and Improves Cognition in Mouse Models of Alzheimer's Disease

Cited by 134 publications

References 51 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

Regulation of ABC Transporters Blood–Brain Barrier

The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease

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1α,25-Dihydroxyvitamin D3Reduces Cerebral Amyloid-β Accumulation and Improves Cognition in Mouse Models of Alzheimer's Disease

Cited by 134 publications

References 51 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

Regulation of ABC Transporters Blood–Brain Barrier

The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease

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Resources

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1α,25-Dihydroxyvitamin D₃Reduces Cerebral Amyloid-β Accumulation and Improves Cognition in Mouse Models of Alzheimer's Disease