Hippocampal pathology and degeneration are also characteristic of hippocampal sclerosis with ageing (HS-ageing), limbic-predominant age-related TDP-43 encephalopathy (LATE), frontotemporal dementia (FTD) and dementia with Lewy bodies. An estimated 60–80% of dementia cases are Alzheimer’s disease (AD), in which the hippocampus, a region of the brain that is essential for learning and memory, is affected early and heavily by neurofibrillary tangle (NFT) pathology and atrophy. Our data suggests that TMEM106B is one of a growing list of major dementia risk genes that affect glial lipid metabolism.Īgeing is the dominant, unifying risk factor for all major forms of dementia, and is thought to constitute the prodromal phase of neurodegeneration. Our study demonstrates that TMEM106B protein abundance is increased with brain ageing in humans, establishes that dementia risk allele rs1990622-A predisposes to TMEM106B fibril formation in the hippocampus, and provides the first evidence that rs1990622-A affects brain lipid homeostasis, particularly myelin lipids. Hippocampal lipids were not significantly affected by APOE genotype, however levels of myelin-enriched sulfatides and hexosylceramides were significantly lower, and polyunsaturated phospholipids were higher, in rs1990622-A carriers after controlling for APOE genotype. Rs1990622-A was also associated with higher TMEM106B fibril content. The increase in TMEM106B levels with ageing was specific to carriers of the rs1990622-A allele in the TMEM106B gene that increases risk for frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, and hippocampal sclerosis with ageing. ![]() TMEM106B, a regulator of lysosomal and oligodendrocyte function, was regulated with greatest effect size. Resultsįorty proteins were associated with age at false discovery rate-corrected P < 0.05, including proteins that regulate cell adhesion, the cytoskeleton, amino acid and lipid metabolism, and ribosomal subunits. Fibrillar C-terminal TMEM106B fragments were isolated using sarkosyl fractionation and quantified by immunoblotting. ANOVA was used to test the effect of major dementia risk alleles in the TMEM106B and APOE genes on the hippocampal proteome and lipidome, adjusting for age, gender, and post-mortem interval. Mass spectrometry-based proteomic and lipidomic analysis of CA1 hippocampus samples from 74 neurologically normal human donors, aged 66–104, was used in combination with multiple regression models and gene set enrichment analysis to identify age-dependent changes in the proteome and lipidome. ![]() The hippocampus was chosen as it is highly susceptible to atrophy with ageing and in several neurodegenerative diseases. ![]() This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal humans over the age of 65. ![]() Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. The risk for dementia increases exponentially from the seventh decade of life.
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