Fight Aging!

All age-related disease is built upon a foundation of damage and dysfunction that stretches as far back as decades prior to the evident manifestation of pathology. The normal operation of cellular metabolism produces forms of molecular damage that take a long time - most of a lifetime - to become prevalent enough to produce obvious change and harm. Researchers here examine the development of Alzheimer's disease from this perspective, with a focus on mitochondrial function, something known to be important in the processes of aging:

Alzheimer's disease (AD) - the most common form of dementia - is a progressive, degenerative disease of the brain. While commonly associated with elderly individuals, this devastating illness is now believed to have its origins much earlier, infiltrating the nervous system decades before the onset of clinical symptoms. Indeed, the greatest obstacle to successful treatment of Alzheimer's is the fact that the disease is typically not recognized until its progress has irreparably ravaged the brain. "Although amyloid plaques and tau neurofibrillary tangles remain as the definitive neuropathological hallmark of the disease, plaques do not correlate at all with degree of cognitive impairment in AD and tangles correlate only slightly. We further know that plaques and tangles are late comers in the cascade of events that cause the dementia of AD."

Mitochondria - membrane-bound organelles found in all eukaryotic organisms - are often called the powerhouses of the cell. Through a process known as oxidative phosphorylation, they produce most of the cell's chemical energy in the form of adenosine triphosphate or ATP. In addition to supplying cellular energy, mitochondria are involved in cell signaling, cellular differentiation, and cell death, as well as in cellular growth and the maintenance of the cell cycle. Because mitochondria play such an important role in the cell, mitochondrial dysfunction has been implicated in a broad range of illness. Unsurprisingly, defects in mitochondrial function more severely affect energy hungry organ systems in the body, particularly muscles, the gastrointestinal tract and the brain. In addition to the role of mitochondrial dysfunction in disease, the gradual degradation of mitochondrial integrity is believed to play a central role in the normal process of aging.

The current study examines tissue from the hippocampus, a structure critical for memory and one severely impacted by the advance of Alzheimer's. Using microarray technology, the authors examined hippocampal tissue from an aging cohort - 44 normal brains from 29-99 years of age, 10 with mild cognitive impairment and 18 with Alzheimer's disease. Gene expression was examined for two sets of genes, 1 encoding mitochondrial DNA and the other, in the nuclear DNA. The two sets of genes both coded for proteins associated with a mitochondrial complex essential for oxidative phosphorylation (OXPHOS), producing energy in the form of ATP for the cell. Intriguingly, while the mitochondrial genes themselves were largely unaffected, the nuclear genes associated with the OXPHOS complex underwent significant modification, depending on the tissues examined. The microarray data revealed substantial down-regulation of nuclear-encoded OXPHOS genes in Alzheimer's tissue, a finding also found in normally aging brains. The same genes, however, were up-regulated in the case of mild cognitive impairment, a precursor to Alzheimer's disease. The authors suggest this effect may be due to a compensatory mechanism in the brain in response to early pathology.

The findings are consistent with earlier work establishing that accumulations of amyloid beta (Aβ) in neurons, a hallmark of Alzheimer's, are directly implicated in mitochondrial dysfunction. The pronounced effect on nuclear-encoded but not mitochondrial-encoded OXPHOS genes may point to dysfunctions in the transport of molecules from the cell nucleus to the mitochondria. "Our work on mitochondria offers the promise of a reliable marker appearing earlier in the course of the disease - one which more closely correlates with the degree of dementia than the current diagnostic of plaques and tangles."

Link: https://www.eurekalert.org/pub_releases/2016-11/asu-poi110416.php