The Alzheimer's disease mitochondrial cascade hypothesis: Progress and perspectives

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1842

Review

Swerdlow, Russell H.^1,2,3,4  Burns, Jeffrey M.^1,2,3  Khan, Shaharyar M.⁵ 

[1] Univ Kansas, Sch Med, Dept Neurol, Kansas City, KS USA

[2] Univ Kansas, Sch Med, Dept Mol & Integrat Physiol, Kansas City, KS USA

[3] Univ Kansas, Sch Med, Alzheimers Dis Ctr, Kansas City, KS USA

[4] Univ Kansas, Dept Biochem & Mol Biol, Sch Med, Kansas City, KS USA

[5] Gencia Corp, Charlottesville, VA USA

关键词: Aging;    Amyloid;    Brain;    Dementia;    Alzheimer's disease;    Mitochondria;   

DOI  :  10.1016/j.bbadis.2013.09.010

来源: Elsevier

【 摘 要 】

Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (A beta) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain A beta at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases. (C) 2013 Elsevier B.V. All rights reserved.

【 授权许可】

Free