Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and cognitive impairment, and there are currently no broadly effective therapies. The underlying pathogenesis is complex, but a growing body of evidence implicates mitochondrial dysfunction as a common pathomechanism involved in many of the hallmark features of the AD brain, such as formation of amyloid-beta (Aβ) aggregates (amyloid plaques), neurofibrillary tangles, cholinergic system dysfunction, impaired synaptic transmission and plasticity, oxidative stress, and neuroinflammation, that lead to neurodegeneration and cognitive dysfunction. Indeed, mitochondrial dysfunction concomitant with progressive accumulation of mitochondrial Aβ is an early event in AD pathogenesis. Healthy mitochondria are critical for providing sufficient energy to maintain endogenous neuroprotective and reparative mechanisms, while disturbances in mitochondrial function, motility, fission, and fusion lead to neuronal malfunction and degeneration associated with excess free radical production and reduced intracellular calcium buffering. In addition, mitochondrial dysfunction can contribute to amyloid-β precursor protein (APP) expression and misprocessing to produce pathogenic fragments (e.g., Aβ1-40). Given this background, we present an overview of the importance of mitochondria for maintenance of neuronal function and how mitochondrial dysfunction acts as a driver of cognitive impairment in AD. Additionally, we provide a brief summary of possible treatments targeting mitochondrial dysfunction as therapeutic approaches for AD.

Keywords: Alzheimer’s disease; calcium buffering; free radical; mitochondria; mitophagy.

Figure 1

Mitochondrial dysfunction as a driver of cognitive impairment in Alzheimer’s disease (AD). Mitochondria are susceptible to various age-associated processes, mutations, and toxic insults such as metal exposure. Damaged mtDNA and other macromolecules accumulate during aging, leading to metabolic impairment. Resultant accumulation of damaged and dysfunctional mitochondria has been reported as an early sign preceding AD and contributing to disease progression. Dysfunctional mitochondria further cause bioenergetic deficiency, intracellular calcium dysregulation, and generation of free radicals leading to oxidative stress, thereby aggravating the effect of Aβ and tau pathology and further exacerbating mitochondrial damage, synaptic dysfunction, cognitive impairment, and memory loss.

Figure 2

Mitochondrial energy metabolism. In healthy cells, the tricarboxylic acid (TCA) cycle works to reduce nicotinamide adenine dinucleotide (NADH) and oxidize succinate molecules, which are further used by the electron transport chain (ETC) to generate an electrochemical gradient between the inner membrane space and matrix. Mitochondrial Complex V (ATP synthase) uses this gradient to produce ATP.

Figure 3

Neuronal mitochondrial trafficking is largely interrupted in AD. (A). In healthy neurons, mitochondria move from the cell body to axons, dendrites, and synapses by an anterograde mechanism, supplying ATP to nerve terminals. Mitochondria then travel back to the cell body from synapses through a retrograde mechanism. (B). In AD neurons, these mechanisms are disrupted primarily due to defective or functionally inactive mitochondria.

Figure 4

Crosstalk between mitochondria and endoplasmic reticulum (ER) during AD. Mitochondria and ER are interconnected via a specialized set of proteins, thus forming specific microdomains called mitochondria-associated ER membranes (MAMs). MAMs play an important role in calcium and lipid homeostasis, mitochondrial dynamics, and autophagy. Perturbations in ER–mitochondria interactions are implicated in AD progression, including neuronal cell death.