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A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state

The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late‐onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2. Intriguingly, APOE4 has been associate...

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Autores principales: Steele, Oliver George, Stuart, Alexander Cameron, Minkley, Lucy, Shaw, Kira, Bonnar, Orla, Anderle, Silvia, Penn, Andrew Charles, Rusted, Jennifer, Serpell, Louise, Hall, Catherine, King, Sarah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796338/
https://www.ncbi.nlm.nih.gov/pubmed/35510513
http://dx.doi.org/10.1111/ejn.15685
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author Steele, Oliver George
Stuart, Alexander Cameron
Minkley, Lucy
Shaw, Kira
Bonnar, Orla
Anderle, Silvia
Penn, Andrew Charles
Rusted, Jennifer
Serpell, Louise
Hall, Catherine
King, Sarah
author_facet Steele, Oliver George
Stuart, Alexander Cameron
Minkley, Lucy
Shaw, Kira
Bonnar, Orla
Anderle, Silvia
Penn, Andrew Charles
Rusted, Jennifer
Serpell, Louise
Hall, Catherine
King, Sarah
author_sort Steele, Oliver George
collection PubMed
description The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late‐onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2. Intriguingly, APOE4 has been associated with neuropathological and cognitive deficits in the absence of Alzheimer's disease‐related amyloid or tau pathology. Here, we review the extensive literature surrounding the impact of APOE genotype on central nervous system dysfunction, focussing on preclinical model systems and comparison of APOE3 and APOE4, given the low global prevalence of APOE2. A multi‐hit hypothesis is proposed to explain how APOE4 shifts cerebral physiology towards pathophysiology through interconnected hits. These hits include the following: neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation. The hits, individually and in combination, leave the APOE4 brain in a vulnerable state where further cumulative insults will exacerbate degeneration and lead to cognitive deficits in the absence of Alzheimer's disease pathology and also a state in which such pathology may more easily take hold. We conclude that current evidence supports an APOE4 multi‐hit hypothesis, which contributes to an APOE4 pathophysiological state. We highlight key areas where further study is required to elucidate the complex interplay between these individual mechanisms and downstream consequences, helping to frame the current landscape of existing APOE‐centric literature.
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spelling pubmed-97963382022-12-30 A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state Steele, Oliver George Stuart, Alexander Cameron Minkley, Lucy Shaw, Kira Bonnar, Orla Anderle, Silvia Penn, Andrew Charles Rusted, Jennifer Serpell, Louise Hall, Catherine King, Sarah Eur J Neurosci Special Issue Reviews The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late‐onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2. Intriguingly, APOE4 has been associated with neuropathological and cognitive deficits in the absence of Alzheimer's disease‐related amyloid or tau pathology. Here, we review the extensive literature surrounding the impact of APOE genotype on central nervous system dysfunction, focussing on preclinical model systems and comparison of APOE3 and APOE4, given the low global prevalence of APOE2. A multi‐hit hypothesis is proposed to explain how APOE4 shifts cerebral physiology towards pathophysiology through interconnected hits. These hits include the following: neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation. The hits, individually and in combination, leave the APOE4 brain in a vulnerable state where further cumulative insults will exacerbate degeneration and lead to cognitive deficits in the absence of Alzheimer's disease pathology and also a state in which such pathology may more easily take hold. We conclude that current evidence supports an APOE4 multi‐hit hypothesis, which contributes to an APOE4 pathophysiological state. We highlight key areas where further study is required to elucidate the complex interplay between these individual mechanisms and downstream consequences, helping to frame the current landscape of existing APOE‐centric literature. John Wiley and Sons Inc. 2022-06-06 2022-11 /pmc/articles/PMC9796338/ /pubmed/35510513 http://dx.doi.org/10.1111/ejn.15685 Text en © 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Special Issue Reviews
Steele, Oliver George
Stuart, Alexander Cameron
Minkley, Lucy
Shaw, Kira
Bonnar, Orla
Anderle, Silvia
Penn, Andrew Charles
Rusted, Jennifer
Serpell, Louise
Hall, Catherine
King, Sarah
A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state
title A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state
title_full A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state
title_fullStr A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state
title_full_unstemmed A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state
title_short A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state
title_sort multi‐hit hypothesis for an apoe4‐dependent pathophysiological state
topic Special Issue Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796338/
https://www.ncbi.nlm.nih.gov/pubmed/35510513
http://dx.doi.org/10.1111/ejn.15685
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