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. Epub 2017 Sep 20 PubMed.

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Comments

  1. This is a very impressive study that revisits the link of ApoE4 to tau pathology, which was first examined by the Allen Roses group with Michel Goedert shortly after ApoE4 was identified as a risk factor for AD (Strittmatter et al., 1994). Oddly, there was little follow-up and the topic languished with regard to biological studies of the interactions of tau and ApoE, so this study certainly will reignite research that should have been followed up after the Strittmatter et al., 1994, paper. 

    References:

    Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, Jakes R, Huang DY, Pericak-Vance M, Schmechel D, Roses AD. Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11183-6. PubMed.

    View all comments by John Trojanowski

  2. Impressive study. However, it is still not clear what impact APOE genotype has in non-AD tauopathies in humans regarding clinical measures. In our series of 13 P301L MAPT patients (Borrego-Écija et al., 2017), the presence of the APOE E4 allele (four APOE4 carriers versus nine APOE4 non-carriers) did not influence the age of onset or duration of disease.

    References:

    Borrego-Écija S, Morgado J, Palencia-Madrid L, Grau-Rivera O, Reñé R, Hernández I, Almenar C, Balasa M, Antonell A, Molinuevo JL, Lladó A, Martínez de Pancorbo M, Gelpi E, Sánchez-Valle R. Frontotemporal Dementia Caused by the P301L Mutation in the MAPT Gene: Clinicopathological Features of 13 Cases from the Same Geographical Origin in Barcelona, Spain. Dement Geriatr Cogn Disord. 2017;44(3-4):213-221. Epub 2017 Sep 22 PubMed.

    View all comments by Raquel Sanchez-Valle

  3. The link between APOE genotype and autophagy has recently received mechanistic reinforcement. We have demonstrated avid, specific binding of ApoE to DNA elements known as "CLEAR" sites, the cis elements bound by transcription factor EB (TFEB), a master regulator of autophagy-related genes (Parcon et al., 2017). 

    ApoE4 was found to bind more efficiently than ApoE3 through both empirical in vitro experiments and through computational modeling in silico analyses. The binding of CLEAR sites by ApoE4 appears to compete with binding by TFEB, thereby reducing the expression of autophagy genes. Evidence consistent with this was found in human brain samples, as well.

    References:

    Parcon PA, Balasubramaniam M, Ayyadevara S, Jones RA, Liu L, Shmookler Reis RJ, Barger SW, Mrak RE, Griffin WS. Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimers Dement. 2018 Feb;14(2):230-242. Epub 2017 Sep 22 PubMed.

    View all comments by Steve Barger

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This paper appears in the following:

News

  1. ApoE4 Makes All Things Tau Worse, From Beginning to End
  2. Rare Luck: Two Copies of ApoE2 Shield Against Alzheimer’s
  3. In Tauopathy, ApoE Destroys Neurons Via Microglia

Research Models

  1. APOE3 Targeted Replacement

Mutations

  1. APOE Loss of Function Variants
  2. APOE R176C (ApoE2)