Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits.
Nicole KoutsodendrisJessica BlumenfeldAyushi AgrawalMichela TragliaBrian GroneMisha ZilberterOscar YipAntara RaoMaxine R NelsonYanxia HaoReuben ThomasSeo Yeon YoonPatrick ArriolaYadong HuangPublished in: Nature aging (2023)
Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.
Keyphrases
- cognitive decline
- high fat diet
- mild cognitive impairment
- traumatic brain injury
- spinal cord
- cerebral ischemia
- mouse model
- adipose tissue
- multiple sclerosis
- early onset
- gene expression
- blood brain barrier
- insulin resistance
- long non coding rna
- poor prognosis
- genome wide
- type diabetes
- dna methylation
- single cell
- skeletal muscle
- copy number