A mitochondrial etiology of Alzheimer and Parkinson disease

Abstract

Background The genetics and pathophysiology of Alzheimer Disease (AD) and Parkinson Disease (PD) appears complex. However, mitochondrial dysfunction is a common observation in these and other neurodegenerative diseases Scope of Review We argue that the available data on AD and PD can be incorporated into a single integrated paradigm based on mitochondrial genetics and pathophysiology. Major Conclusions Rare chromosomal cases of AD and PD can be interpreted as affecting mitochondrial function, quality control, and mitochondrial DNA (mtDNA) integrity. mtDNA lineages, haplogroups, such haplogroup H5a which harbors the mtDNA tRNAGln A8336G variant, are important risk factors for AD and PD. Somatic mtDNA mutations are elevated in AD, PD, and Down Syndrome and Dementia (DSAD) both in brains and also systemically. AD, DS, and DSAD brains also have reduced mtDNA ND6 mRNA levels, altered mtDNA copy number, and perturbed Aβ metabolism. Classical AD genetic changes incorporated into the 3XTg-AD (APP, Tau, PS1) mouse result in reduced forebrain size, life-long reduced mitochondrial respiration in 3XTg-AD males, and initially elevated respiration and complex I and IV activities in 3XTg-AD females which markedly declines with age. General Significance Therefore, mitochondrial dysfunction provides a unifying genetic and pathophysiology explanation for AD, PD, and other neurodegenerative diseases.

A mitochondrial bioenergetic etiology of disease

“…For example, factors that increase mitochondrial ROS production would increase the mtDNA mutation rate and lead to premature organ failure. Increased mtDNA somatic mutation levels have been documented in ischemic heart disease (34), AD brains (35-37), PD brains (38,39), Huntington disease brains (40), and Down syndrome with dementia (DSAD) brains (37). In AD and DSAD brains, elevated somatic mtDNA base substitution mutations have been correlated with reduced mtDNA copy number and ND6 transcript levels (37).…”

Mitochondrial retrograde signaling regulates neuronal function

“…Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment. T he human brain constitutes approximately 2% of body weight but consumes 20% of available oxygen because of its high energy demand (1). Mitochondria are abundant in neurons and generate the majority of cellular ATP through the action of the mitochondrial ATP synthase complex.…”

Neurological disorders and therapeutics targeted to surmount the blood–brain barrier

“…Localized inflammation is also responsible for deleterious effects in Alzheimer's disease and PD because of increased mitochondrial reactive oxygen species. 52 This finding opens up a potential new avenue of therapeutic investigation into neurodegenerative diseases. The drugs currently available for PD treat the disease symptomatically, either by mimicking dopaminergic actions or by enhancing the duration of action of dopamine.…”