Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Abstract

Dysfunction of cell bioenergetics is a common feature of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Disrupted energy utilization implicates mitochondria at its nexus. This review summarizes some of the evidence that points to faulty mitochondrial function in AD and highlights past and current therapeutic development efforts. Classical neuropathological hallmarks of disease (β‐amyloid and τ) and sporadic AD risk genes (APOE) may trigger mitochondrial disturbance, yet mitochondrial dysfunction may incite pathology. Preclinical and clinical efforts have overwhelmingly centred on the amyloid pathway, but clinical trials have yet to reveal clear‐cut benefits. AD therapies aimed at mitochondrial dysfunction are few and concentrate on reversing oxidative stress and cell death pathways. Novel research efforts aimed at boosting mitochondrial and bioenergetic function offer an alternative treatment strategy. Enhancing cell bioenergetics in preclinical models may yield widespread favourable effects that could benefit persons with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

Metabolic regulation of neurodifferentiation in the adult brain

“…For example, the autism spectrum disorder (ASD) has been linked to impaired neuronal development, since patient-derived reprogrammed cells showed impaired neuronal maturation [193], while a reduction of neurogenesis and impaired differentiation into neurons was reported in epileptic patients [194,195]. Interestingly, reduced adult hippocampal neurogenesis has recently been observed in patients with Alzheimer's disease [23], and mitochondrial dysfunction is a key feature in Alzheimer's pathology [196], further pointing to an important connection between neurogenesis and mitochondria.…”

Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death

“…Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive neuronal loss and the presence of hallmark neuropathology of neurofibrillary tangles and amyloid plaques, especially in the hippocampus and cortex [1]. Defective glucose utilization and energy metabolism is one of the best-documented abnormalities in AD, implicating an essential role of mitochondrial dysfunction in the pathogenesis of AD [2]. Indeed, mitochondrial dysfunction and oxidative stress have been found as an early and prominent feature in AD patients and AD animal models [2,3].…”

“…Defective glucose utilization and energy metabolism is one of the best-documented abnormalities in AD, implicating an essential role of mitochondrial dysfunction in the pathogenesis of AD [2]. Indeed, mitochondrial dysfunction and oxidative stress have been found as an early and prominent feature in AD patients and AD animal models [2,3]. However, the underlying mechanism remains elusive.…”

Therapeutics for dementia and Alzheimer's disease: New directions for precision medicine

“…Previously, the few dementia‐associated therapies aimed at mitochondrial dysfunction have focused on reversing oxidative stress and cell death pathways. Despite the clear contributory effects that impaired bioenergetics have in early disease progression and phenotypic outcome, research efforts aimed at boosting bioenergetic function remain to be developed and provide a window of opportunity in drug discovery (Perez Ortiz & Swerdlow, ). Continued identification and characterization of binding partners for APP and Aβ also increase the appreciation of the complexity in the pathways related to APP metabolism and their involvement in disease.…”