ABCA7 and the altered lipidostasis hypothesis of Alzheimer's disease

Abstract

We propose the altered lipidostasis hypothesis of Alzheimer's disease (AD). It holds that vulnerable neurons of the entorhinal region generate a neurodegenerative lipid during normal function, adenosine triphosphate–binding cassette transporter subfamily A member 7 (ABCA7) protects from AD pathogenesis by removing it out of the cell, generation of the lipid increases with age, and the minimal amount of ABCA7 needed to dispose of the rising volumes of the lipid also increases with age. A survey of ABCA7 protein levels in the hippocampus or parietal cortex of 123 individuals with or without AD neuropathology showed that individuals with low ABCA7 developed AD neuropathology at a younger age, those with intermediate ABCA7 developed it later, and individuals who developed it very late had high ABCA7, the same as the youngest controls. ABC transporters closely similar to ABCA7 protect cells by removing toxic lipids. ABCA7 may have analogous functions. The hypothesis predicts lipidosis and membrane protein dysfunction in neurons with low ABCA7. Further work will identify the neurodegenerative lipid and determine approaches to exploit ABCA7 for therapeutic purposes.

Role of ABCA7 in Human Health and in Alzheimer’s Disease

“…Interestingly, no ABCA7 mRNA signal was initially detected in total human brain samples but this result was later refuted by several groups demonstrating mRNA and protein expression of ABCA7 in human and murine samples of the different cell types present in the brain [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Therefore, it is now largely demonstrated that ABCA7 is expressed in neurons, astrocytes, microglia, endothelial cells of the blood–brain barrier (BBB), brain pericytes, not only in mice but also in humans ([ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]— , and , accessed on 31 December 2020).…”

“…Abca7 is mainly expressed by neurons and microglia in human and mouse brains [ 23 , 80 , 81 , 82 ]. Both isoforms described in Section 2.2 are observed by western blots in brain samples of healthy donors and AD patients [ 25 ].…”

“…In humans, it was demonstrated more recently in brain samples that levels of ABCA7 modestly but significantly decrease with normal aging [ 23 ]. A significant association between ABCA7 SNP (rs3764650) and cognitive decline was only observed in females in a longitudinal study including 3267 females and 3026 males [ 70 ].…”

“…These observations confirmed the link between ABCA7 and Aβ peptides in humans but do not explain if this is mainly due to a decrease in Aβ production, or an increase of the clearance mediated by microglia across the BBB. A recent and elegant study from Lyssenko et al investigated ABCA7 protein level in different Braak stages in AD patients and controls [ 23 ]. They observed that patients with low levels of ABCA7 are more prone to develop early AD than patients with the highest ABCA7 levels.…”

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

“…ABCA7 is highly expressed in the brain, predominantly in neurons and microglia ( Zhang et al, 2014 ). Reduced ABCA7 levels are observed in AD brain ( Lyssenko and Praticò, 2020 ) and hippocampus of mice on a high fat diet ( Zou et al, 2020 ). Contrary to ABCA1, transcription of ABCA7 is downregulated when cholesterol levels are high in the cell ( Iwamoto et al, 2006 ).…”