Accumulation of neutral lipids in dystrophic neurites surrounding amyloid plaques in Alzheimer's disease

Alzheimer's disease (AD) is characterized by the formation β-amyloid (Aβ) deposited neuritic plaques. Recent evidence suggests that abnormal lipid metabolism and accumulation could serve as biomarkers for neurodegenerative diseases, including AD. Tubular endoplasmic reticulum protein, reticulon 3 (RTN3), plays a crucial role in the development of neuritic plaque and lipid metabolism in AD brains. In present study, we sought to investigate a potential association between neutral lipid accumulation and AD pathology. BODIPY 500/510 dye was used to label neutral lipid surrounding Aβ plaques in APPNL-G-F mouse and AD postmortem brains samples. Immunofluorescent images were captured using confocal microscope and co-localization between lipid metabolism proteins and neutral lipids were evaluated. Lipid accumulation in Aβ plaque surrounding dystrophic neurites (DNs) was observed in the cortical region of AD mouse models and human AD brain samples. The neutral lipid staining was not co-localized with IBA1-labeled microglia or GFAP-labeled astrocytes, but it was co-labeled with VAMP2 and neurofilament. We further showed that neutral lipids were accumulated in RTN3 immunoreactive DNs. Both the neutral lipids accumulation and RIDNs formation showed age-dependent patterns in surrounding amyloid plaques. Mechanistic studies revealed that RTN3 likely contributes to the enrichment of neutral lipids near plaques by interacting with heat shock cognate protein 70 (HSC70) and diminishing its function in chaperone-mediated lipophagy. Our study provides immunohistochemical evidence of neutral lipids being enriched in DNs near amyloid plaques. Our findings shed light on RTN3-mediaed lipid accumulation in AD neuropathology and provide fresh insights into the role of RTN3 in neurodegenerative diseases. Potential mechanism of how a deficiency in RTN3 induces larger BODIPY+ DNs and amyloid plaques in Alzheimer's disease. The absence of RTN3 could alleviate the interaction between RTN3 and HSC70. This, in turn, would potentiate the regulatory capacity of HSC70 over lipophagy and lipolysis, furnishing numerous autophagic vacuoles with membrane components. This cascade of events holds the potential to stimulate the augmented production and subsequent release of Aβ peptides and tau protein. [Display omitted] •Neutral lipids were accumulated in dystrophic neurites near amyloid plaques of AD brain.•RTN3 immunoreative dystrophic neurites-associated neutral lipid accumulation is an age-depe