Effects of ApoE in Tau-Mediated Neurodegeneration
David M. Holtzman
Washington University in St. Louis, MO, USA
APOE genotype is the strongest genetic risk factor for Alzheimer's disease (AD). The E4 allele increases risk for AD and the E2 allele decreases risk relative to the E3 allele. There is strong evidence that a large part of the effect of apoE on AD pathogenesis is via its ability to influence the onset and accumulation of aggregated forms of Abeta in the brain parenchyma through its regulation of Abeta aggregation and clearance. There is emerging evidence that ApoE may also mediate some of its effects in AD and other tauopathies via influencing both tau as well as the brain's innate immune response. We recently found that ApoE strongly enhances neurodegeneration in a mouse model of tauopathy (P301S Tau transgenic - Tg mice) with ApoE4 having the greatest effects. Very little to no neurodegeneration was seen in the absence of ApoE. The enhanced neurodegeneration seen with ApoE was accompanied by a strong neurodegenerative type microglial and astrocyte response and similar responses could be observed in cultures of primary neurons expressing P301S human tau cultured in the presence of glia expressing ApoE. We have been attempting to elucidate the mechanism of these results as well as determining whether the lowering of ApoE in P301S Tau Tg mice could be neuroprotective. In preliminary experiments, we have crossed P301S Tau Tg mice with mice transgenic mice that overexpress the low density lipoprotein receptor (LDLR) in the brain. So far, we have note that at 9 months of age, P301S Tau Tg mice have significant tauopathy and brain atrophy. In P301S Tau/LDLR Tg mice, ApoE levels are markedly lowered and there is significantly less brain atrophy. Additional analysis to sort out the inflammatory response and the mechanism of these effects are underway.
Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C; Alzheimer's Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527.
Funding: NIH NS090934, AG047644, and the JPB Foundation