The Alzheimer's disease mitochondrial cascade hypothesis: an update - PubMed (original) (raw)
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The Alzheimer's disease mitochondrial cascade hypothesis: an update
Russell H Swerdlow et al. Exp Neurol. 2009 Aug.
Abstract
In 2004 we proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD). Our hypothesis assumed sporadic and autosomal dominant AD are not etiologically homogeneous, considered evidence that AD pathology is not brain-limited, and incorporated aging theory. The mitochondrial cascade hypothesis asserted: (1) inheritance determines mitochondrial baseline function and durability; (2) mitochondrial durability influences how mitochondria change with age; and (3) when mitochondrial change reaches a threshold, AD histopathology and symptoms ensue. We now review the reasoning used to formulate the hypothesis, discuss pertinent interim data, and update its tenants. Readers are invited to consider the conceptual strengths and weaknesses of this hypothesis.
Figures
Figure 1
The mitochondrial cascade hypothesis.
Figure 2
Non-synonymous open reading frame polymorphisms in 50 individuals who under went CO1, CO2, CO3, and CO4 gene sequencing. The listed polymorphisms from the four genes analyzed define 11 distinct CO enzyme complexes among the 50 individuals. Synonymous polymorphisms, untranslated region (UTR) polymorphisms, and variation in the other 9 CO genes are not listed. The nucleotide numbers for CO1, CO2, and CO3 are from the Cambridge mtDNA sequence. The CO4 polymorphism occurs at nucleotide 77 of the mRNA. AA=amino acid.
Figure 3
Cytochrome oxidase activities from15 cyb rid cell lines prepared by transferring AD subject platelet mitochondria to NT2 cells depleted of endogenous mtDNA. Enzyme activities are plotted as a function of the platelet donor’s age. The ages of the subjects roughly estimates the ages at which their AD developed, and suggests those with lower cytochrome oxidase activities had a younger age of onset.
Figure 4
An individual’s cytochrome oxidase activity at a given age reflects their baseline activity minus an age-dependent activity decline. Activity baselines and rates of decline vary between individuals. For heuristic purposes we have shown a cytochrome oxidase activity threshold below which AD symptoms manifest. Those with high baseline activities and slow decline rates would remain above the disease threshold until a very advanced age, while those with lower baseline activities and more rapid decline rates would cross the threshold at a much younger age. CO=cytochrome oxidase.
Figure 5
Hypothetical scheme in which Akt drives cell growth and division under conditions of trophic stimulation and low cell energy levels, and drives cell growth without division under conditions of trophic stimulation and higher energy levels. GSK3β=glycogen synthase kinase 3 beta; mTORC2=mammalian target of rapamycin complex 2; P=phospho.
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