The Alzheimer's Disease Mitochondrial Cascade Hypothesis

Abstract

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-β (Aβ) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce Aβ 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.

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

“…Ab signaling is linked with peroxynitrite production. 1,15 Ab or peroxynitrite trigger mitochondrial fragmentation, which in turn can lead to bioenergetic failure, impaired Ca 2 þ homeostasis, synaptic injury, axonal transport defects and neuronal cell death. 16,20 To investigate whether nanoceria would prevent Ab-mediated mitochondrial fragmentation, mitochondrial morphology was visualized by fluorescence microscopy in transfected neurons expressing DsRed2-Mito.…”

“…[10][11][12] Finally, peroxynitrite can irreversibly inhibit complexes I and IV of the mitochondrial respiratory chain. 11,13 Because mitochondria have a critical role in neurons as energy producers to fuel vital processes such as synaptic transmission and axonal transport, 14 and mitochondrial dysfunction is a well-documented and early event in AD, 15 it is important to consider how peroxynitrite and nitrosative stress affect mitochondria. Although the ultimate cause of mitochondrial dysfunction in AD remains unclear, an imbalance in mitochondrial fission and fusion is one possibility.…”

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

“…3 In contrast, there is growing evidence that mitochondrial damage and oxidative stress lead to activation of the Aβ cascade. 3,6,7 In regard to inflammatory cells, microglia can form a protective network for the brain to control neurotrophic factors, limit oxidative stress, and foster neuronal regeneration. Microglia also may limit the deposition and toxicity of Aβ and promote neuronal survival.…”

Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca 2+ cross-talk

“…It has been reported recently (14) that presenilins are enriched in ER mitochondriaassociated membranes, i.e., the ER membrane domains interacting closely with mitochondria and endowed with key players of the Ca 2+ -handling machinery (15). This finding, together with the generally accepted concept that mitochondrial deficits are key events in most neurodegenerative diseases (16,17), and more specifically in AD (18,19), led us to investigate the effect of presenilins on ER-mitochondria cross-talk.…”