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This study conducted comprehensive lipidomic and proteomic analyses of brain tissue from patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD), revealing significant overlap in lipid metabolism disruptions between these two neurodegenerative diseases. Both conditions showed reduced cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, cholesterol esters, and other lipid species, with accompanying changes in lysosomal proteins and lipid-processing enzymes. While patterns were broadly similar across FTLD subtypes, GRN-associated FTLD-TDP and Pick's disease showed the most extensive alterations, with some subtype-specific differences such as reduced triglycerides uniquely in Pick's disease.
Why it matters
These findings suggest that lipid metabolism dysregulation represents a common pathway in multiple forms of dementia, potentially offering new therapeutic targets that could be relevant across different neurodegenerative diseases. Understanding these shared metabolic disruptions may lead to treatments addressing fundamental disease mechanisms rather than disease-specific pathology.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick disease’s, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.
Source: Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease