---
title: "ABCA7 loss impairs microglial lysosomes, lipid handling and phagocytosis in iPSC models of Alzheim"
id: "biorxiv-11-the-alzheimer-s-disease-risk-gene-abca7-regulates-microglial-lysosomal-and"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-11-the-alzheimer-s-disease-risk-gene-abca7-regulates-microglial-lysosomal-and"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.16.759681v1?rss=1"
published_at: "2026-10-19T10:27:13.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# ABCA7 loss impairs microglial lysosomes, lipid handling and phagocytosis in iPSC models of Alzheim
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-11-the-alzheimer-s-disease-risk-gene-abca7-regulates-microglial-lysosomal-and
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.16.759681v1?rss=1)
- **Published At:** 2026-10-19T10:27:13.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Investigators used CRISPR/Cas9 to generate isogenic **ABCA7** knockout (ABCA7-KO) and wild-type iPSCs, and differentiated them into neurons, astrocytes and microglia for proteomic profiling. - Proteomics showed the largest changes in induced microglia (iMGs); the ABCA7-KO iMG proteome was depleted for lysosome-related proteins and altered lipid-handling pathways. - Functional assays in ABCA7-KO iMGs demonstrated reduced lysosomal activity (reduced DQ-BSA activity and decreased LAMP1+ area) and impaired **phagocytosis** compared with isogenic controls. - The ABCA7-KO iMGs had increased inflammatory markers, including elevated MHC proteins CD1A and CD1E and elevated IL-18, indicating a proinflammatory shift in the absence of ABCA7. - Lipidomic and proteomic integration indicated disrupted phospholipid steady-state metabolism, increased lipid peroxidation, accumulation of polyunsaturated triacylglycerols, and enlarged lipid droplets in ABCA7-KO iMGs. - Inhibiting triacylglycerol synthesis mitigated lysosomal defects and reduced lipid droplet phenotypes, suggesting a mechanistic link between triacylglycerol accumulation and lysosomal impairment. - The study used CRISPR correction of the AD risk variant rs3752246 in patient-derived iPSCs; corrected iMGs showed that the rs3752246 mutant state recapitulated lysosomal dysfunction seen in ABCA7-KO cells. - In tri-culture systems combining iNs, iAs and iMGs, ABCA7 deficiency confined to microglia exacerbated neuronal measures relevant to Alzheimer’s disease, including increased tau phosphorylation and reduced synapse number. - The source did not report clinical trial data, human cohort statistics, or in vivo efficacy; mechanistic rescue experiments were limited to cellular models and biochemical assays described in the manuscript.
## Clinical Analysis & Structured Key Points
The Alzheimer's disease risk gene ABCA7 regulates microglial lysosomal and lipid homeostasis and promotes phagocytosis to maintain neuronal health | bioRxiv Skip to main content New Results The Alzheimer's disease risk gene ABCA7 regulates microglial lysosomal and lipid homeostasis and promotes phagocytosis to maintain neuronal health View ORCID Profile Sarah E Heuer , View ORCID Profile Fasih M. Ahsan , Gizem Terzioglu , Arnab Misra , Duc Duong , Chaitanya Katkar , View ORCID Profile Martin M. Giera , View ORCID Profile Rik van der Kant , View ORCID Profile Nicholas Seyfried , Tracy L Young-Pearse doi: https://doi.org/10.64898/2026.10.16.759681 Sarah E Heuer 1 Ann Romney Center for Neurologic Disease, Mass General Brigham & Harvard Medical School, Boston, MA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sarah E Heuer Fasih M. Ahsan 1 Ann Romney Center for Neurologic Disease, Mass General Brigham & Harvard Medical School, Boston, MA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Fasih M. Ahsan Gizem Terzioglu 1 Ann Romney Center for Neurologic Disease, Mass General Brigham & Harvard Medical School, Boston, MA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Arnab Misra 1 Ann Romney Center for Neurologic Disease, Mass General Brigham & Harvard Medical School, Boston, MA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Duc Duong 2 Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Chaitanya Katkar 3 Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Martin M. Giera 4 Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Martin M. Giera Rik van der Kant 3 Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Rik van der Kant Nicholas Seyfried 2 Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nicholas Seyfried Tracy L Young-Pearse 1 Ann Romney Center for Neurologic Disease, Mass General Brigham & Harvard Medical School, Boston, MA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: tpearse{at}bwh.harvard.edu Abstract Info/History Metrics Supplementary material Preview PDF Abstract Background: Loss of function mutations in the lipid transporter ABCA7 have been linked to increased risk for late onset Alzheimer's disease (AD). Although rare and common variants in ABCA7 associated with AD alter the coding sequence and are predicted to impair protein function, the precise cell-type consequences of ABCA7 deficiency remain incompletely defined. Methods: We used CRISPR/Cas9 gene editing to generate induced pluripotent stem cells (iPSCs) that were deficient for ABCA7 (ABCA7-KO) and their wild-type (ABCA7-WT) isogenic counterparts and subsequently performed unbiased proteomics on differentiated astrocytes (iAs), neurons (iNs) and microglia (iMGs). ABCA7 deficiency in iMGs produced the largest proteomic changes, so we therefore conducted additional functional analyses to define its effects on microglial lysosomal activity, phagocytosis, and lipid metabolism. In addition, we leveraged CRISPR/Cas9 to correct the ABCA7 rs3752246 AD risk variant in patient-derived iPSCs and compared proteomic and functional phenotypes between corrected iMGs and isogenic mutant carriers. Finally, we examined the functional consequence of ABCA7-deficient microglia on neurons. Results: ABCA7-KO iMGs were deficient for proteins involved in lysosome function, measured by down-regulated lysosomal proteomic signatures, as well as reduced DQ-BSA activity and reduced LAMP1+ area. Additionally, ABCA7-KO iMGs displayed impaired phagocytic capacity and increased inflammatory markers, including MHC proteins CD1A and CD1E, and IL-18,. Multi-omic integration of lipidomic and proteomic profiles nominated a dysregulated metabolic network characterized by altered phospholipid steady-state metabolism and increased lipid peroxidation in ABCA7-KO iMGs. This was complemented by an accumulation of polyunsaturated triacylglycerols and lipid droplets, suggesting that ABCA7 deficiency disrupts intracellular lipid dynamics. This was supported by the alleviation of lysosomal and lipid droplet phenotypes through the inhibiting the synthesis of triacylglycerols. Concordantly, proteomic and functional analyses revealed lysosomal dysfunction in rs3752246-mutant iMGs, suggesting a shared ABCA7-dependent mechanism underlying AD risk. Tri-cultures of iNs, iAs and iMGs revealed that ABCA7 deficiency in iMGs worsened AD-relevant neuronal measures such as tau phosphorylation and synapse number. Conclusions: This work supplies evidence for the important role of ABCA7 in microglia and provides unique insights into the molecular and functional consequences of reduced ABCA7 function in lysosomal and lipid regulation, paving a path forward to a more comprehensive understanding of AD molecular subtypes and personalized therapeutics. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared National Institute on Aging, https://ror.org/049v75w11 , R01AG055909 , U54AG090669 , R01AG055909 , F32AG099445 , T32AG000222 National Institute of Neurological Disorders and Stroke , R01NS142331 Alzheimer's Association, https://ror.org/0375f4d26 , Zenith Award to Tracy Young-Pearse BrightFocus Foundation , A2025005F Chan Zuckerberg Initiative , DAF2022-250616 Dutch Research Council , Vidi 2021 09150172110086 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Back to top Previous Next Posted October 19, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. 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Giera , Rik van der Kant , Nicholas Seyfried , Tracy L Young-Pearse bioRxiv 2026.10.16.759681; doi: https://doi.org/10.64898/2026.10.16.759681 Share This Article: Copy Citation Tools The Alzheimer's disease risk gene ABCA7 regulates microglial lysosomal and lipid homeostasis and promotes phagocytosis to maintain neuronal health Sarah E Heuer , Fasih M. Ahsan , Gizem Terzioglu , Arnab Misra , Duc Duong , Chaitanya Katkar , Martin M. 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