Mitochondrial Dysfunction as a Causative Factor in Alzheimer’s Disease-Spectrum Disorders: Lymphocytes as a Window to the Brain

Abstract

: Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will further increase with longer life expectancy. The AD brain is marked by severe neurodegeneration, such as the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems, especially in the hip- pocampus and cerebral cortex. Recent findings highlight the important role of mitochondrial dys- function and increased oxidative stress in the pathophysiology of late-onset Alzheimer’s disease (LOAD). These alterations are not only observed in the brain of AD patients but also in the periph- ery. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as peripheral markers for the detection of AD in blood cells e.g. lymphocytes. We evaluate recent findings regarding impaired mitochondrial function comprising mitochondrial respiration, reduced complex activities of the respiratory chain and altered Mitochon- drial Membrane Potential (MMP) in lymphocytes as well as in neurons. Finally, we will question whether these mitochondrial parameters might be suitable as an early peripheral marker for the de- tection of LOAD but also for the transitional stage between normal aging and Dementia, “Mild Cognitive Impairment” (MCI).

Peripheral Mitochondrial Dysfunction: A Potential Contributor to the Development of Metabolic Disorders and Alzheimer’s Disease

“…This form of AD, called sporadic AD, has been reported to be a result of apolipoprotein E4; a significant risk factor, which may accelerate Aβ formation and plaque deposition. Further establishment of the hypothesis came from the findings of multiple preclinical studies with cells and transgenic animal models showing Aβ plaque deposition as a causative pathogenesis of AD [43,58].…”

Talk to Me—Interplay between Mitochondria and Microbiota in Aging

“…Therefore, constant loss of MMP as observed in the aging process might reflect reduced ETC capacity, reflected in the loss of activity and stability of ETC complexes during aging [ 23 , 28 ]. This decline is specific for different tissues with reduced complex III and IV activity in the heart muscle and diminished complex I and III function in brain, liver, and skeletal muscle, as well as parts of our immune system such as CD4+ T-helper cells [ 17 , 29 , 30 ]. Analysis of mitochondrial function in the skeletal muscle of older subjects revealed a drop in ATP levels [ 31 , 32 ] of approximately 50% compared to younger controls, which might also be the cause for sarcopenia typically associated with aging.…”

N1-methylation of adenosine (m1A) in ND5 mRNA leads to complex I dysfunction in Alzheimer’s disease

“…Mitochondrial dysfunction is one of the major pathologic hallmarks in sporadic Alzheimer's disease (AD) (19)(20)(21), the most common form of AD (99 % of all AD cases). Age is the greatest known risk factor and mitochondria have long been implicated in the aging process and age-related diseases.…”

“…Several alterations in mitochondrial function were associated with AD, such as reduced mitochondrial membrane potential, reduced ATP levels, enhanced reactive oxygen species (ROS) as well as impaired mitochondrial morphology, mitochondrial fusion and mitophagy (20,(22)(23)(24)(25)(26). These pathological changes are assumed to be strongly associated with reduced effectivity of the respiratory chain especially complex I (22,(27)(28)(29)(30).…”