The Alzheimer's disease mitochondrial cascade hypothesis

Abstract

We first proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD) in 2004. Our core assumptions were a person's genes determine baseline mitochondrial function and durability, this durability determines how mitochondria change with advancing age, and critical changes in mitochondrial function initiate other pathologies characteristic of AD. Since then several lines of investigation report data consistent with or supportive of our hypothesis. In particular, AD endophenotype studies suggest a strong maternal genetic contribution, and links between mitochondrial function, tau phosphorylation, and amyloid-beta (Abeta) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce Abeta thus far have had at best very limited clinical benefits; our hypothesis identifies alternative therapeutic targets. While placing mitochondria at the apex of an AD cascade certainly remains controversial, it is increasingly accepted by the AD research community that mitochondria play an important role in the late-onset forms of the disease. Even if the mitochondrial cascade hypothesis proves incorrect, considering its assumptions could potentially advance our understanding of sporadic, late-onset AD.

Figure 1

The cybrid technique. A cultured cell line (A) is depleted of endogenous mtDNA to create ρ0 cells (B). Cytoplasts containing mitochondria (C) but not nuclei are mixed with ρ0 cells in the temporary presence of a detergent that disrupts cell membranes. When cell membranes reform, mixing ρ0 cell and cytoplast contents produces cells with a ρ0 cell line nucleus, cytoplast mitochondria, and cytoplast mtDNA (D).

Figure 2

The mitochondrial cascade hypothesis. In our hypothesis, which applies to sporadic AD, mitochondria are at the apex of the cascade. In autosomal dominant cases we also predict mitochondria may mediate the effects of presenile brain amyloidosis. Used with permission from reference [16].

Figure 3

Relationship between platelet donor age and cytochrome oxidase activity in AD cybrid cell lines. Younger platelet donors likely have a younger age of AD onset than older platelet donors. Cybrid cell lines made using platelets from younger AD subjects tend towards lower cytochrome oxidase Vmax activities. Used with permission from reference [16].