Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.
Yang ShiMelissa ManisJustin M LongKairuo WangPatrick M SullivanJavier Remolina SerranoRosa HoyleDavid M HoltzmanPublished in: The Journal of experimental medicine (2019)
Chronic activation of brain innate immunity is a prominent feature of Alzheimer's disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of ptau pathology is also driven by microglia. In addition, we found that APOE, the strongest genetic risk factor for AD, regulates neurodegeneration predominantly by modulating microglial activation, although a minor role of apoE in regulating ptau and insoluble tau formation independent of its immunomodulatory function was also identified. Our results suggest that therapeutic strategies targeting microglia may represent an effective approach to prevent disease progression in the setting of tauopathy.
Keyphrases
- neuropathic pain
- inflammatory response
- mouse model
- cognitive decline
- high glucose
- high fat diet
- diabetic rats
- spinal cord
- drug induced
- lipopolysaccharide induced
- machine learning
- cerebrospinal fluid
- lps induced
- signaling pathway
- white matter
- genome wide
- resting state
- multiple sclerosis
- type diabetes
- skeletal muscle
- functional connectivity
- small molecule
- adipose tissue
- blood brain barrier
- binding protein