ABCA7-dependent Neuropeptide-Y signalling is a resilience mechanism required for synaptic integrity in Alzheimer’s disease

Tayran, Hüseyin; Yilmaz, Elanur; Bhattarai, Prabesh; Min, Yuhao; Wang, Xue; Ma, Yiyi; Nelson, Nastasia; Kassara, Nada; Cosacak, Mehmet Ilyas; Dogru, Ruya Merve; Reyes-Dumeyer, Dolly; Reddy, Joseph S; Qiao, Min; Flaherty, Delaney; Teich, Andrew F.; Gunasekaran, Tamil Iniyan; Yang, Zikun; Tosto, Giuseppe; Vardarajan, Badri N; İş, Özkan; Ertekin-Taner, Nilüfer; Mayeux, Richard; Kizil, Caghan

doi:10.1101/2024.01.02.573893

Cited by 2 publications

(1 citation statement)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ABCA7 is a member of the A subfamily of ABC transmembrane proteins 20 with high sequence homology to ABCA1, the primary lipid transporter responsible for cholesterol homeostasis and high-density lipoprotein genesis in the brain 21 . ABCA7 effluxes both cholesterol and phospholipids to APOA-I and APOE in in vitro studies 22–26 and has been shown to be a critical regulator of lipid metabolism, immune cell functions, and amyloid processing 27–31 . To date, study of ABCA7 LoF has been predominantly pursued in rodent knock-out models or in non-neural mammalian cell lines.…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

Haploinsufficiency and Alzheimer’s Disease: The Possible Pathogenic and Protective Genetic Factors

Bagyinszky,

2024

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a complex neurodegenerative disorder influenced by various genetic factors. In addition to the well-established amyloid precursor protein (APP), Presenilin-1 (PSEN1), Presenilin-2 (PSEN2), and apolipoprotein E (APOE), several other genes such as Sortilin-related receptor 1 (SORL1), Phospholipid-transporting ATPase ABCA7 (ABCA7), Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), Phosphatidylinositol-binding clathrin assembly protein (PICALM), and clusterin (CLU) were implicated. These genes contribute to neurodegeneration through both gain-of-function and loss-of-function mechanisms. While it was traditionally thought that heterozygosity in autosomal recessive mutations does not lead to disease, haploinsufficiency was linked to several conditions, including cancer, autism, and intellectual disabilities, indicating that a single functional gene copy may be insufficient for normal cellular functions. In AD, the haploinsufficiency of genes such as ABCA7 and SORL1 may play significant yet under-explored roles. Paradoxically, heterozygous knockouts of PSEN1 or PSEN2 can impair synaptic plasticity and alter the expression of genes involved in oxidative phosphorylation and cell adhesion. Animal studies examining haploinsufficient AD risk genes, such as vacuolar protein sorting-associated protein 35 (VPS35), sirtuin-3 (SIRT3), and PICALM, have shown that their knockout can exacerbate neurodegenerative processes by promoting amyloid production, accumulation, and inflammation. Conversely, haploinsufficiency in APOE, beta-secretase 1 (BACE1), and transmembrane protein 59 (TMEM59) was reported to confer neuroprotection by potentially slowing amyloid deposition and reducing microglial activation. Given its implications for other neurodegenerative diseases, the role of haploinsufficiency in AD requires further exploration. Modeling the mechanisms of gene knockout and monitoring their expression patterns is a promising approach to uncover AD-related pathways. However, challenges such as identifying susceptible genes, gene–environment interactions, phenotypic variability, and biomarker analysis must be addressed. Enhancing model systems through humanized animal or cell models, utilizing advanced research technologies, and integrating multi-omics data will be crucial for understanding disease pathways and developing new therapeutic strategies.

show abstract

ABCA7-dependent Neuropeptide-Y signalling is a resilience mechanism required for synaptic integrity in Alzheimer’s disease

Cited by 2 publications

References 110 publications

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

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

Haploinsufficiency and Alzheimer’s Disease: The Possible Pathogenic and Protective Genetic Factors

Contact Info

Product

Resources

About