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Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease

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Abstract

The major genetic risk factor for sporadic Alzheimer’s disease (AD) is the lipid binding and transporting carrier protein apolipoprotein E, epsilon 4 allele (ApoE4). One of the unsolved mysteries of AD is how the presence of ApoE4 elicits this age-associated, currently incurable neurodegenerative disease. Recently, we showed that ApoE4 acts as a transcription factor and binds to the promoters of genes involved in a range of processes linked to aging and AD disease pathogenesis. These findings point to novel therapeutic strategies for AD and aging, resulting in an extension of human healthspan, the disease-free and functional period of life. Here, we review the effects and implications of the putative transcriptional role of ApoE4 and propose a model of Alzheimer’s disease that focuses on the transcriptional nature of ApoE4 and its downstream effects, with the aim that this knowledge will help to define the role ApoE4 plays as a risk factor for AD, aging, and other processes such as inflammation and cardiovascular disease.

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Abbreviations

AD:

Alzheimer’s disease

APP:

β-amyloid precursor protein

ApoE:

Apolipoprotein E

SirT1:

Sirtuin1

PP2A:

Protein phosphatase 2A

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Acknowledgements

We thank the members of the DEB laboratory for helpful comments and discussions and Rowena Abulencia for administrative assistance. Our research work is supported in part by grants from the Buck-Impact Circle Funds (R.V.R), the Lucas Brothers Foundation (R.V.R), the Four Winds Foundation (D.E.B), the Marin Community Foundation (D.E.B), The John and Bonnie Strauss Foundation (R.V.R and D.E.B), and The Katherine Gehl Foundation (R.V.R and D.E.B).

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  1. The Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94945, USA

    Veena Theendakara, Clare A. Peters-Libeu, Dale E. Bredesen & Rammohan V. Rao

  2. Easton Laboratories for Neurodegenerative Disease Research, UCLA, Los Angeles, CA, 90025, USA

    Dale E. Bredesen

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  1. Veena Theendakara
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Theendakara, V., Peters-Libeu, C.A., Bredesen, D.E. et al. Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease. Mol Neurobiol 55, 5243–5254 (2018). https://doi.org/10.1007/s12035-017-0757-2

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