Summary: New research strengthens earlier findings that mutations affecting mitochondrial function may play a crucial role in the onset and progression of Alzheimer’s disease.
Source: Arizona State University.
On Nov. 25, 1901, a 51-year-old woman was admitted to a Frankfurt hospital with strikingly unusual symptoms: erratic behavior, paranoia, auditory hallucinations, disorientation and severe memory loss. She could only begin to write her name, managing just “Mrs.” before she could not continue. “I have lost myself,” she told her physician.
That patient, Auguste Deter, gradually withdrew from the world and died on April 9, 1906. Her physician, Alois Alzheimer, carefully examined her brain and identified the distinctive amyloid plaques and neurofibrillary tangles that characterize the disease now known as Alzheimer’s. Her case became the first formal diagnosis of this disorder.
Today Alzheimer’s disease affects an estimated 5 million people in the United States and is expected to grow substantially in the coming decades. Among the leading causes of death, Alzheimer’s remains unique in that it cannot yet be prevented, cured, or effectively halted in its progression.
Researchers at the ASU-Banner Neurodegenerative Disease Research Center (NDRC) and the Biodesign Center for Bioenergetics report new findings in the journal Alzheimer’s and Dementia. Diego Mastroeni, Paul Coleman and colleagues examined how mitochondria — the cell’s energy-producing organelles — relate to Alzheimer’s disease, building on earlier studies that implicated mitochondrial dysfunction in neurodegeneration.
The study focuses on gene expression changes tied to mitochondrial energy production. Specifically, it shows that in Alzheimer’s patients, many nuclear-encoded genes that support mitochondrial respiration and oxidative phosphorylation (OXPHOS) are expressed at reduced levels. In contrast, those same genes appear up-regulated in people with mild cognitive impairment (MCI), an intermediate stage often preceding Alzheimer’s. The researchers interpret this increase in MCI as a likely compensatory response by the brain during earlier stages of dysfunction.
Assault on identity
Alzheimer’s disease is the most common form of dementia and a progressive, degenerative brain disorder. Although symptoms usually emerge in later life, mounting evidence indicates the pathological processes begin decades earlier, long before symptoms are clinically apparent. This early, silent phase poses the biggest challenge to effective treatment: by the time the disease is recognized, substantial and often irreversible brain damage has already occurred.
The illness commonly starts with subtle memory lapses and gradually erodes language, judgment and orientation. Age is the strongest risk factor, but genetics and conditions that affect vascular health—such as high cholesterol, heart disease, stroke and hypertension—also increase risk. Alzheimer’s is a leading cause of death in older adults and comprises roughly 60–70% of dementia diagnoses.
Historically, a definitive diagnosis required post-mortem identification of amyloid plaques and neurofibrillary tangles. New imaging methods can detect some of these markers in living patients, but current experts caution that plaques and tangles are late-stage features that do not reliably correlate with the severity of cognitive impairment. Identifying earlier, more predictive molecular changes remains a major research priority.
Quick energy
Mitochondria are membrane-bound organelles present in nearly all eukaryotic cells and are critical for producing the bulk of cellular energy as ATP through oxidative phosphorylation. Beyond energy production, mitochondria regulate cell signaling, differentiation, growth, the cell cycle and programmed cell death.
Because the brain consumes about 20% of the body’s energy while representing only about 2% of body weight, even modest disruptions in mitochondrial function can disproportionately affect neural tissue. Mitochondrial dysfunction has been implicated in many conditions across neurology and medicine, including stroke, epilepsy, neurodevelopmental and psychiatric disorders, metabolic disease, and various forms of dementia including Alzheimer’s.
Mitochondria are also unique because they retain their own genome (mtDNA), a remnant of their evolutionary origin as free-living bacteria that became endosymbionts in ancestral eukaryotic cells. Over time, much of mitochondrial machinery was transferred to nuclear DNA, leaving a complementary set of genes split between the mitochondrial and nuclear genomes.
Broken genes
The ASU-led study analyzed hippocampal tissue, a brain region essential for memory and especially vulnerable in Alzheimer’s disease. Using microarray technology, researchers profiled gene expression in hippocampi from an aging cohort: 44 cognitively normal controls aged 29–99, 10 subjects with amnestic mild cognitive impairment (MCI), and 18 confirmed Alzheimer’s cases.
They compared two groups of genes that code for components of the OXPHOS complexes: those encoded by mitochondrial DNA and those encoded by nuclear DNA. The results were striking: mitochondrial-encoded genes showed little change across groups, while nuclear-encoded OXPHOS genes were significantly down-regulated in Alzheimer’s tissue. In contrast, many of these nuclear-encoded genes were up-regulated in MCI samples, consistent with an early compensatory response.
These patterns align with prior evidence that accumulation of amyloid-beta in neurons disrupts mitochondrial function. The selective alteration of nuclear-encoded OXPHOS genes — but not mitochondrial-encoded genes — may indicate defects in the transport of proteins or regulatory signals from the nucleus to mitochondria, or in the nuclear regulation of mitochondrial biogenesis and maintenance.
Paul Coleman and colleagues suggest that measuring changes in nuclear-encoded mitochondrial genes could offer earlier, more reliable markers of disease progression than plaques or tangles. Importantly, the study implies a therapeutic opportunity: strategies aimed at restoring normal expression or function of nuclear-encoded OXPHOS genes might slow or blunt Alzheimer’s progression if applied early enough.
Further research will be required to clarify the precise molecular mechanisms linking nuclear gene regulation, mitochondrial dysfunction, aging and the progressive cognitive decline seen in Alzheimer’s. Still, by highlighting an early, potentially reversible component of disease biology, this work points to promising directions for diagnosis and intervention.
Source: Richard Harth — Arizona State University
Image Source: Image credited to Kelvinsong.
Original Research: Abstract for “Nuclear but not mitochondrial-encoded OXPHOS genes are altered in aging, mild cognitive impairment, and Alzheimer’s disease” by Diego Mastroeni et al., published in Alzheimer’s & Dementia. Published online October 25, 2016. doi:10.1016/j.jalz.2016.09.003
Abstract
Nuclear but not mitochondrial-encoded OXPHOS genes are altered in aging, mild cognitive impairment, and Alzheimer’s disease
Introduction
This study describes expression profiles of mitochondrial DNA and nuclear DNA genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes (I–V) in the hippocampus from young controls, age-matched controls, subjects with mild cognitive impairment (MCI), and Alzheimer’s disease (AD) patients.
Methods
Hippocampal tissues from 44 non-AD controls (NC), 10 amnestic MCI, and 18 Alzheimer’s disease (AD) cases were analyzed on Affymetrix Hg-U133 plus 2.0 microarrays.
Results
Microarray data revealed significant down-regulation of nuclear-encoded OXPHOS genes in AD. In contrast, many of the same nuclear-encoded genes were up-regulated in MCI subjects compared to AD and NC cases. No significant differences were observed in the majority of mitochondrial DNA (mtDNA) genes identified on the array between AD, NC, and MCI subjects, with the exception of mt-ND6.
Discussion
The findings suggest that restoring expression of nuclear-encoded OXPHOS genes during aging could be a viable strategy for slowing AD progression.
“Nuclear but not mitochondrial-encoded OXPHOS genes are altered in aging, mild cognitive impairment, and Alzheimer’s disease” by Diego Mastroeni, Omar M. Khdour, Elaine Delvaux, Jennifer Nolz, Gary Olsen, Nicole Berchtold, Carl Cotman, Sidney M. Hecht, and Paul D. Coleman. Alzheimer’s & Dementia. Published online October 25, 2016. doi:10.1016/j.jalz.2016.09.003