Mitochondria and Mitochondrial Cascades in Alzheimer's Disease

Abstract

Decades of research indicate mitochondria from Alzheimer's disease (AD) patients differ from those of non-AD individuals. Initial studies revealed structural differences, and subsequent studies showed functional deficits. Observations of structure and function changes prompted investigators to consider the consequences, significance, and causes of AD-related mitochondrial dysfunction. Currently, extensive research argues mitochondria may mediate, drive, or contribute to a variety of AD pathologies. The perceived significance of these mitochondrial changes continues to grow, and many currently believe AD mitochondrial dysfunction represents a reasonable therapeutic target. Debate continues over the origin of AD mitochondrial changes. Some argue amyloid-β (Aβ) induces AD mitochondrial dysfunction, a view that does not challenge the amyloid cascade hypothesis and that may in fact help explain that hypothesis. Alternatively, data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD. This review considers studies and data that inform this area of AD research.

Keywords: Alzheimer’s disease; bioenergetics; cascade; cytochrome oxidase; mitochondria.

Fig.1

Secondary mitochondrial cascade. Secondary mitochondrial cascades are compatible with the amyloid cascade hypothesis, and could mediate Aβ toxicity. As illustrated, Aβ can directly introduce various AD-associated functional changes and pathologies, and directly or indirectly cause mitochondrial dysfunction. Aβ-induced mitochondrial dysfunction, in turn, could further contribute to or initiate additional AD-associated functional changes and pathologies.

Fig.2

Primary mitochondrial cascade. A primary mitochondrial cascade is incompatible with the amyloid cascade hypothesis. Under this scenario, impaired mitochondrial function and associated bioenergetic changes alter Aβ homeostasis and lead to an accumulation of Aβ. Aβ may or may not in turn contribute to the development of other AD-associated functional changes and pathologies.

Fig.3

Could mitochondrial function influence recognized AD biomarker changes? Studies that track dynamic biomarker shifts suggest changes in Aβ (lower CSF levels or plaque accumulation) precede tau changes (lower CSF tau or tangle accumulation beyond the medial temporal regions). Reductions in brain volume (hippocampal volumes) follow Aβ and tau changes. Declining memory abilities and dementia eventually occur. Additional data, though, suggest metabolism-relevant characteristics may distinguish high AD risk individual from low AD risk individuals before detectable Aβ changes occur. Mitochondrial function also changes with advancing age. It is reasonable to consider whether mitochondria define thresholds at which these biomarker changes begin to manifest.