Could provide therapeutic target

Persons with APOE-ɛ4 isoforms had reduced mitochondrial, synaptic, and oxidative stress proteins, and some of these proteins were associated with cognitive performance, an autopsy series found.

Compared with APOE-ɛ4 noncarriers, people with APOE-ɛ4 had reduced mitochondrial biogenesis proteins PGC-1α and SIRT3, reported Jiong Shi, MD, PhD, of Barrow Neurological Institute at St. Joseph Hospital and Medical Center in Phoenix, Arizona, and coauthors.

Mitochondrial dynamic fusion and fission proteins MFN1, MFN2, and DLP1 also were reduced in APOE-ɛ4 carriers. Oxidative stress proteins SOD2 and Foxo3a were lower, as were synaptic proteins PSD95 and Syn1. Some mitochondrial proteins were strongly associated with cognitive performance.

“We demonstrated that ApoE-ɛ4 downregulated mitochondrial biogenesis, dynamics, and its antioxidative stress proteins,” Shi and colleagues wrote in Neurology. “ApoE-ɛ4 was associated with reduced synaptic proteins and impaired cognitive function.”

“Mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of Alzheimer’s disease,” they added.

APOE-ɛ4 is a risk factor for late-onset Alzheimer’s disease and is implicated in impaired cerebral physiology. About 25% of the U.S. population and 60% of those with Alzheimer’s are carriers. Changes in brain structure in carriers are evident as early as infancy.

Mitochondrial dysfunction plays a key role in multiple degenerative neurologic disorders, including Parkinson’s disease, Huntington’s disease, and Alzheimer’s. The 2004 publication of the “mitochondrial cascade” hypothesis in sporadic late-onset Alzheimer’s disease noted that the earlier “amyloid cascade” hypothesis was based on infrequent autosomal dominant Alzheimer’s variants. The mitochondrial cascade hypothesis posited that inherited electron transport chain properties set basal rates of reactive oxygen species production, with subsequent effects on beta-amyloid production, apoptosis, and abnormal cell-cycle responses to neuronal progenitor cells with tau phosphorylation and neurofibrillary tangles, the hallmarks of Alzheimer’s disease.

Mitochondrial dysfunction is associated with reduced mitochondrial metabolism, abnormal calcium dynamics, and increased oxidation and apoptosis. These are, in turn, participants in observed loss of synapses, defective axonal transport, and cognitive decline as described in a murine model that found reduction of DRP1 decreased production of phosphorylated tau. Another murine study found SIRT3 overexpression improved mitochondrial function and ATP production that had been damaged by beta-amyloid, suggesting a role in Alzheimer’s pathogenesis.

The effects of the APOE-ɛ4 isoform on mitochondrial proteins and their function in developing Alzheimer’s disease has remained unclear at this stage of transitional research, however.

In their analysis, Shi and colleagues analyzed post-mortem tissue and pre-mortem clinical data from the Arizona Alzheimer’s Disease Center Clinical Core, including APOE-ɛ4 carriers (n=21) and non-carriers (n=25), with median postmortem interval of 3.2 hours. Samples from the middle temporal gyrus were used to determine protein levels. Pre-mortem data included cognitive measures of global as well as temporal and frontal lobe function.

Average age (85-89 years) and sex (female 44%-48%) were not significantly different between carriers and non-carriers. Mini Mental State Examination (MMSE) values were 21.4 in carriers and 26.2 in noncarriers (P=0.026).

Among APOE-ɛ4 carriers, the prevalence of Alzheimer’s, mild cognitive impairment, and normal cognition was 38.1%, 28.6%, and 33.3%, respectively. For non-carriers, the respective proportions were 32.0%, 40.0%, and 28.0%.

Mitochondrial proteins and cognitive functioning scores were correlated. PGC-1α, SIRT3, and MFN1 were significantly associated with scores on tests that assessed global cognitive function (Mattis Dementia Rating Scale), frontal and temporal function (60-item Boston Naming Test), and temporal lobe function (Auditory Verbal Learning Test, total learning). DLP1 also was tied to Mattis Dementia Rating Scale scores.

By cognitive diagnosis, levels of mitochondrial fusion and fission proteins MFN1, MFN2, and DLP1 were lower in those with Alzheimer’s disease than those who were cognitively normal or had mild cognitive impairment.

“These data provide the most compelling evidence to date that directly links APOE-ɛ4 to mitochondrial alterations in the human brain and confirm the importance of mitochondrial homeostasis, thereby providing clues for future mechanistic studies,” noted Xiongwei Zhu, PhD, of Case Western Reserve University in Cleveland, Ohio, and co-authors, in an accompanying editorial.

The study has several limitations, Zhu and colleagues noted. The researchers examined only limited brain areas, making it hard to generalize the findings, they pointed out. APOE-ɛ4 carriers also had lower MMSE scores, “which likely suggests more degeneration in these brains,” they added. “Therefore, the possibility that the reported changes are due to greater severity of disease rather than APOE effect should be considered.”

  1. Persons with APOE-ɛ4 isoforms had reduced mitochondrial, synaptic, and oxidative stress proteins, and some of these proteins were associated with cognitive performance, an autopsy series found.

  2. Changes in mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and may provide novel therapeutic targets for Alzheimer’s prevention and treatment, the researchers suggested.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This work was funded by the National Institute on Aging, the Flinn Foundation, and the Barrow Neurological Foundation.

Shi was funded by the Flinn Foundation and the Barrow Neurological Foundation.

Zhu reported no disclosures.

Cat ID: 33

Topic ID: 82,33,404,485,730,33,192,255,925