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The Interplay Between Apolipoprotein E4 and the Autophagic–Endocytic–Lysosomal Axis

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Abstract

Since its discovery as a genetic risk factor for Alzheimer’s disease, the APOE4 allele has been linked to the majority of the pathological findings associated with the disease progression. These include abnormalities of the endocytic, autophagic, and lysosomal machineries, which begin at the most early stages of Alzheimer’s disease development. Considering that these three vesicular systems share common features and, in fact, comprise an interconnected cargo-trafficking and degradation network, some of the effects of APOE4 are interrelated, while others are system-specific. In turn, APOE4-driven impairments of endocytosis, autophagy, and lysosomal activity influence various aspects of Alzheimer’s disease pathology, ranging from Aβ generation and clearance to neuronal loss and cognitive deficits. This review discusses the detrimental effects of APOE4 on the endocytic–autophagic–lysosomal axis in the context of Alzheimer’s disease, as well as the various mechanisms underlying them.

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Abbreviations

Aβ:

amyloid beta

AD:

Alzheimer’s disease

APP:

amyloid precursor protein

apoE:

apolipoprotein E

Atg:

autophagy-related protein

FAD:

familial AD

mTOR1:

mammalian target of rapamycin (complex 1)

NFT:

neurofibrillary tangles

PI3K:

phosphoinositide 3-kinase

PIP2:

phosphatidylinositol bisphosphate

PS1 and PS2:

presenilin 1 and 2

SAD:

sporadic AD

synj1:

synaptojanin 1

TR:

target replacement

VLDL:

very low density lipoprotein

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Acknowledgments

The Prajs-Drimmer Institute for degenerative diseases supported this work. We wish to thank Eya Wolfson and Shira Solomon for critically reading the manuscript.

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Authors and Affiliations

  1. Department of Neurobiology, Tel-Aviv University, 69978, Ramat-Aviv, Israel

    E. Schmukler, D. M. Michaelson & R. Pinkas-Kramarski

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  1. E. Schmukler
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  2. D. M. Michaelson
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  3. R. Pinkas-Kramarski
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Correspondence to R. Pinkas-Kramarski.

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Highlights

• APOE4 is the most prevalent genetic risk factor for late-onset Alzheimer’s disease (AD).

• Impaired endocytosis, autophagy, and lysosomal activities are observed in AD and possibly contribute to disease progression.

• ApoE isoforms differentially affect endocytic, autophagic, and lysosomal activities.

• ApoE isoforms may affect Aβ production and clearance by mechanisms that involve the endocytic–autophagic–lysosomal axis.

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Schmukler, E., Michaelson, D.M. & Pinkas-Kramarski, R. The Interplay Between Apolipoprotein E4 and the Autophagic–Endocytic–Lysosomal Axis. Mol Neurobiol 55, 6863–6880 (2018). https://doi.org/10.1007/s12035-018-0892-4

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  • DOI: https://doi.org/10.1007/s12035-018-0892-4

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