A newly published study reveals a compelling connection between a key genetic risk factor for late-onset Alzheimer’s disease (LOAD) and abnormal lipid metabolism in microglia, the resident immune cells of the brain. Researchers have identified that the LOAD-risk allele of the gene PICALM instigates an unexpected accumulation of lipid droplets (LDs) within microglia, a phenotype that could contribute to neurodegenerative processes. This discovery opens a fresh avenue into understanding how genetic susceptibilities translate into cellular dysfunction and disease progression in Alzheimer’s.
The PICALM gene, previously linked to Alzheimer’s risk through genome-wide association studies, has been primarily known for roles in endocytosis and membrane trafficking. However, this investigation extends its functional repertoire to lipid biology within microglia. Utilizing induced pluripotent stem cell (iPSC)-derived microglia (iMGs) harboring the PICALM risk and non-risk alleles, scientists observed a striking two- to sevenfold increase in intracellular LDs in risk allele carriers. This effect was visualized and quantified using BODIPY staining, a fluorescent probe targeting neutral lipids, underscoring a profound lipid metabolic disturbance.
Further delving into cholesterol metabolism, the study employed filipin staining to detect unesterified cholesterol and revealed elevated free cholesterol levels in microglia bearing the risk allele. Cholesterol esters, which are cholesterol derivatives stored in LDs alongside triacylglycerols (TGs), have been implicated in lipid droplet biogenesis. The lipid droplet accumulation in PICALM risk-allele microglia correlates with increased levels of these storage lipids, suggesting a link between genetic variation, cholesterol handling defects, and lipid storage-organelles proliferation.
Crucially, pharmacological manipulation demonstrated that inhibiting long-chain acyl-CoA synthetase via triacsin C leads to a significant reduction of LD formation. This finding not only confirms the nature of these droplets as bona fide lipid storage entities but also hints at enzymatic steps amenable to therapeutic intervention. Moreover, the involvement of lysosomal dysfunction in this process was suggested by altered expression of lysosomal genes, and microscopic analysis showed increased lysosome and LD colocalization, pointing to impaired lipid degradation pathways as a driver of lipid overload.
The researchers further interrogated whether PICALM expression levels directly mediate these lipid anomalies. Activation of PICALM expression via CRISPR activation (CRISPRa) in risk allele microglia normalized LD levels, whereas knocking down PICALM in non-risk microglia elevated LD formation. This dose-dependent effect solidifies PICALM’s pivotal role in maintaining lipid homeostasis within microglia and identifies reduced PICALM function as a mechanistic link to lipid droplet accumulation associated with Alzheimer’s risk.
Lipidomic profiling revealed a selective enrichment of triacylglycerols among the altered lipid species in PICALM risk-allele microglia, with over thirty TG species significantly elevated. This lipid signature mirrors the previously characterized lipid-laden microglia (LDAMs) and the lipid abnormalities seen in APOE4-associated microglial states, hallmark features of Alzheimer’s pathology. Restoration of PICALM expression reversed these lipidomic disruptions, suggesting therapeutic potential in targeting this pathway to rebalance microglial lipid metabolism.
Interestingly, although PICALM has been shown to facilitate lipid transfer between neurons and astrocytes in other systems such as Drosophila and rat astrocytes, similar lipid transfer assays in these human microglia models showed no difference between risk and non-risk allele carriers. This cell-type-specific distinction implies that PICALM’s impact on lipid droplet formation in microglia may operate independently of lipid uptake from neurons, instead reflecting intrinsic defects in lipid metabolism or degradation within these immune cells.
The implication of lysosomal dysregulation in the observed phenotype highlights the intersection of lipid storage and autophagic processes. Lysosomes, essential for the catabolism of complex lipids, appeared functionally compromised in PICALM risk microglia, potentially leading to lipid droplet accumulation. Given microglial roles in debris clearance and immune surveillance, such an intracellular metabolic imbalance may impair their neuroprotective functions and exacerbate neurodegeneration.
Taken together, these data present a novel pathological mechanism by which the PICALM Alzheimer’s risk allele predisposes specifically microglia to lipid metabolic dysfunction through promoting excessive lipid droplet accumulation and lysosomal perturbation. This insight adds a vital layer to the complex molecular etiology of Alzheimer’s, shifting focus onto the metabolic health and immune competency of resident brain macrophages.
The study’s use of CRISPR-based gene editing and activation provides robust causal evidence linking PICALM expression to cellular lipid phenotypes and offers compelling proof-of-concept for modulating this pathway therapeutically. By restoring PICALM function, it may be possible to reverse lipid droplet buildup, thereby normalizing microglial physiology and potentially mitigating downstream neuroinflammatory cascades contributing to Alzheimer’s disease progression.
Future research building on these findings will be instrumental in dissecting the precise molecular pathways downstream of PICALM that govern microglial lipid metabolism. Moreover, the distinct cell-specific effects observed underscore the complexity and heterogeneity of glial lipid handling in the brain, warranting careful contextual analysis in designing targeted interventions.
As Alzheimer’s disease continues to impose an immense societal and healthcare burden worldwide, insights such as these, which illuminate the metabolic vulnerabilities ingrained in genetic risk factors, pave the way for novel biomarker development and innovative therapeutic strategies. This study stands as a landmark in bridging genetic susceptibility to cellular lipid dysregulation within microglia, expanding our understanding of neurodegenerative disease pathophysiology.
In sum, unraveling how PICALM risk alleles disrupt microglial lipid homeostasis via lipid droplet pathology and lysosomal dysfunction offers an exciting and viral new perspective on Alzheimer’s disease mechanisms. These discoveries spotlight microglia lipid metabolism as a promising target for future interventions aimed at halting or reversing the devastating cognitive decline afflicting millions.
Subject of Research: Alzheimer’s disease; microglial lipid metabolism; genetic risk factors
Article Title: PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia
Article References:
Kozlova, A., Zhang, S., Sudwarts, A. et al. PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia. Nature (2025). https://doi.org/10.1038/s41586-025-09486-x
Image Credits: AI Generated
