The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis

Abstract

To promote new thinking of the pathogenesis of Alzheimer's disease (AD), we examine the central role of mitochondrial dysfunction in AD. Pathologically, AD is characterized by progressive neuronal loss and biochemical abnormalities including mitochondrial dysfunction. Conventional thinking has dictated that AD is driven by amyloid beta pathology, per the Amyloid Cascade Hypothesis. However, the underlying mechanism of how amyloid beta leads to cognitive decline remains unclear. A model correctly identifying the pathogenesis of AD is critical and needed for the development of effective therapeutics. Mitochondrial dysfunction is closely linked to the core pathological feature of AD: neuronal dysfunction. Targeting mitochondria and associated proteins may hold promise for new strategies for the development of disease-modifying therapies.According to the Mitochondrial Cascade Hypothesis, mitochondrial dysfunction drives the pathogenesis of AD, as baseline mitochondrial function and mitochondrial change rates influence the progression of cognitive decline.

Inhibiting amyloid beta (1–42) peptide-induced mitochondrial dysfunction prevents the degradation of synaptic proteins in the entorhinal cortex

“…Mitochondrial dysfunction resulting in increased ROS production and oxidative stress precedes the formation of neuritic plaques and neurofibrillary tangles, and is thought to contribute substantially to the earliest stages of AD and the onset of cognitive decline and memory loss (Uttara et al, 2009;Wang et al, 2014;Tönnies and Trushina, 2017;Ashleigh et al, 2022).…”

“…The selective vulnerability of the EC to early AD-related synaptic damage and neurodegeneration ( Du et al, 2004 ; Velayudhan et al, 2013 ; Zhou et al, 2016 ), may reflect the dysregulation of neural mechanisms including NMDA glutamate receptors that contribute to learning and memory ( Olajide et al, 2021 ). Aβ can accumulate in mitochondria where it impairs mitochondrial dynamics and upregulates oxidative stress by impairing mitochondrial respiratory function and the production of adenosine triphosphate (ATP) ( Wang et al, 2014 , 2020 ; Ashleigh et al, 2022 ). Further, activation of NMDA receptors by hAβ 1–42 can lead to increases in calcium influx, the rapid facilitation of AMPA glutamate receptor responses, and hyperexcitability that increases metabolic demands on mitochondria, ultimately culminating in oxidative stress and synaptic dysfunction ( Findley et al, 2019 ; Guo et al, 2020 ; Wang et al, 2020 ).…”

“…Mitochondrial dysfunction resulting in increased ROS production and oxidative stress precedes the formation of neuritic plaques and neurofibrillary tangles, and is thought to contribute substantially to the earliest stages of AD and the onset of cognitive decline and memory loss ( Uttara et al, 2009 ; Wang et al, 2014 ; Tönnies and Trushina, 2017 ; Ashleigh et al, 2022 ). We have shown here that short-term exposure of wild-type EC slices to hAβ 1–42 results in deficits in mitochondrial respiration, and have provided evidence that oxidative stress associated with increased ROS is a major factor in the rapid degeneration of key pre- and post-synaptic proteins in the EC.…”

“…Synaptic transmission relies heavily on mitochondria that generate energy through ATP and nicotinamide adenine dinucleotide (NAD +), maintain calcium homeostasis and buffering, and regulate cell signaling ( Calkins et al, 2011 ; Akhter et al, 2017 ; Pickett et al, 2018 ). Perturbation of mitochondrial functions may contribute directly to impaired synaptic transmission in early AD ( Cavallucci et al, 2013 ; Akhter et al, 2017 ; Olajide et al, 2017a ; Xiao et al, 2017 ; Pickett et al, 2018 ; Khosravi and Harner, 2020 ), and Aβ can disrupt mitochondrial energy production and lead to increases in the synthesis of reactive oxygen species (ROS) and oxidative damage ( Calkins et al, 2011 ; Hampel et al, 2021 ; Olajide et al, 2021 ; Ashleigh et al, 2022 ). Cellular ROS are natural by-products of mitochondrial aerobic respiration that result predominantly from leakage of electrons at complexes I and III of the electron transport chain.…”

Connecting aging biology and inflammation in the omics era

“…The expression of senescent factors, SASPs in particular, creates an inflammatory milieu within the brain believed to modulate neuroimmune processes while also compromising the integrity of the BBB ( 169 , 170 ). The aggregation of misfolded proteins, including Aβ plaques and tau neurofibrillary tangles, may also promote neuronal and glial senescent phenotypes ( 171 ), as do other common facets of neurodegeneration, such as mitochondrial dysfunction and abnormal proteostasis ( 22 , 172 , 173 ). Although less direct, cellular senescence within the periphery and its associated SASP may also prime microglia and affect neurodegenerative processes through the immune-brain axis.…”