CSF biomarker analysis of ABCA7 mutation carriers suggests altered APP processing and reduced inflammatory response

Duchateau, Lena; Küҫükali, Fahri; De Roeck, Arne; Wittens, Mandy M. J.; Temmerman, Joke; Weets, Ilse; Timmers, Maarten; Engelborghs, Sebastiaan; Bjerke, Maria; Sleegers, Kristel

doi:10.1186/s13195-023-01338-y

Cited by 3 publications

(2 citation statements)

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“… 40 The VNTR expansion was moreover associated with lower Aβ 40 , Aβ 42, sAPPα, sAPPβ, and YKL‐40 CSF levels. 41 This expanded VNTR might therefore (partially) explain the GWAS signals in Caucasians.…”

Section: Abca7 Ad‐associated Variantsmentioning

confidence: 98%

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The ABC's of Alzheimer risk gene ABCA7

Duchateau,

Wawrzyniak,

Sleegers

2024

Alzheimer's & Dementia

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Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7’s identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode‐of‐action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain.Highlights Alzheimer's risk‐increasing variants in ABCA7 can be found in up to 7% of AD patients. We review the recently characterized protein structure of ABCA7. We present latest insights in genetics, expression patterns, and functions of ABCA7.

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Section: Abca7 Ad‐associated Variantsmentioning

confidence: 98%

“… 73 A significant increase in T‐tau levels in PTC carriers were further supported in a recent study on CSF levels in ABCA7 mutation carriers. 41 …”

Section: Abca7 Ad‐associated Variantsmentioning

confidence: 99%

The ABC's of Alzheimer risk gene ABCA7

Duchateau,

Wawrzyniak,

Sleegers

2024

Alzheimer's & Dementia

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Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances

von Maydell,

Wright,

Bonner

et al. 2023

Preprint

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ABCA7 loss-of-function (LoF) variants dramatically increase the risk of Alzheimer’s disease (AD), yet the pathogenic mechanisms and the cell types affected by this loss remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 humanpost-mortemsamples from the prefrontal cortex (PFC) of ABCA7 LoF carriers and matched control individuals. ABCA7 LoF variants were associated with perturbed gene clusters in all major cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed profound perturbations in gene clusters related to lipid metabolism, mitochondrial function, DNA damage, and NF-kB signaling. Given the known role of ABCA7 as a lipid transporter, we reasoned that ABCA7 LoF may mediate neuronal dysfunction by altering the lipidome, and evaluated lipid changes by untargeted mass-spectrometry. Indeed, ABCA7 LoF inpost-mortemhuman PFC and iPSC-derived neurons showed widespread changes to the lipidome, including increased triacylglycerides and altered abundance of multiple phospholipid species. Consistent with these observations, assays onpost-mortemhuman PFC and iPSC-derived ABCA7 LoF neurons (iNs) showed increased levels of mitochondrial dysfunction, DNA damage, and NF-kB activation, suggesting that ABCA7 LoF is a causal mediator of these disruptions in neurons. This study provides a detailed atlas of ABCA7 LoF in the human brain and suggests that lipid dysregulation in neurons may be an underlying insult by which ABCA7 LoF increases AD risk.One-Sentence SummaryABCA7 loss-of-function, associated with increased risk for Alzheimer’s, causes mitochondrial dysfunction, DNA damage, and lipid disruptions in neurons.

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Alzheimer's Disease and Effects of ABCA7 Polymorphisms: A Review

Gialama,

Siokas,

Liampas

et al. 2024

J. Integr. Neurosci.

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Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the main cause of dementia. Its etiology remains largely unclear, though genetic and environmental factors appear to confer susceptibility to AD development. This study assessed the role of ATP-binding Cassette A Subfamily 7 (ABCA7) genetic polymorphisms, as ongoing research suggests they have a role in the development of AD. We conducted a PubMed, Google Scholar, and Scopus search to identify and assess all AD studies examining ABCA7 variants in different populations and ethnicities. The last search was conducted on February 8, 2023. Inclusion and exclusion criteria were applied and only the studies that met the inclusion criteria were included in this review. Seventeen studies were finally included. According to the results, ABCA7 variants infer different risks for AD among populations with different ancestries. African American populations show a higher risk for AD, carrying the five novel variants rs115550680, rs142076058, rs10405305, rs3764647, and rs567222111. Asian populations also have an increased risk for AD, harboring three variants. ABCA7 genetic variability contributes to AD development and shows racial disparities. African American and Asian populations seem to be at greater risk of developing AD. These results may assist future research efforts for the early and accurate diagnosis of AD. Moreover, further exploration of the mechanisms of ABCA7 in the context of AD could identify potential therapeutic targets.

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CSF biomarker analysis of ABCA7 mutation carriers suggests altered APP processing and reduced inflammatory response

Cited by 3 publications

References 61 publications

The ABC's of Alzheimer risk gene ABCA7

The ABC's of Alzheimer risk gene ABCA7

Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances

Alzheimer's Disease and Effects of ABCA7 Polymorphisms: A Review

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