Drug Target to Alleviate Mitochondrial Dysfunctions in Alzheimer's Disease: Recent Advances and Therapeutic Implications

Abstract

Alzheimer's disease (AD) is a severe progressive neurodegenerative condition associated with neuronal damage and reduced cognitive function that primarily affects the aged worldwide. While there is increasing evidence suggesting that mitochondrial dysfunction is one of the most significant factors contributing to AD, its accurate pathobiology remains unclear. Mitochondrial bioenergetics and homeostasis are impaired and defected during AD pathogenesis. However, the potential of mutations in nuclear or mitochondrial DNA encoding mitochondrial constituents to cause mitochondrial dysfunction has been considered since it is one of the intracellular processes commonly compromised in early AD stages. Additionally, electron transport chain dysfunction and mitochondrial pathological protein interactions are related to mitochondrial dysfunction in AD. Many mitochondrial parameters decline during aging, causing an imbalance in reactive oxygen species (ROS) production, leading to oxidative stress in age-related AD. Moreover, neuroinflammation is another potential causative factor in AD-associated mitochondrial dysfunction. While several treatments targeting mitochondrial dysfunction have undergone preclinical studies, few have been successful in clinical trials. Therefore, this review discusses the molecular mechanisms and different therapeutic approaches for correcting mitochondrial dysfunction in AD, which have the potential to advance the future development of novel drug-based AD interventions.

Keywords: Alzheimer’s disease; ROS.; drug target; mitochondria; mitochondrial dysfunction; therapeutic approaches.

Fig. (1)

The molecular pathophysiology of AD. APP is cleaved by α-secretases and β-secretases, resulting in the accumulation of neurotoxic Aβ in plaques. NFTs are aggregates of pTau protein in the nervous system. AD is characterized by synaptic disruption and memory impairment caused by Aβ plaques and NFTs.

Fig. (2)

Mitochondrial biogenesis and function. Mitochondria play an important role in ATP synthesis through oxidative phosphorylation. Glycolysis occurs in the cytosol and is responsible for the initial breakdown of glucose into pyruvate. The mtDNA encodes 37 genes involved in synthesizing the respiratory chain and ATP production. Additional proteins are imported into mitochondria by the translocases of the inner (TIM) and outer (TOM) membranes, which are present in the IMM and OMM and are responsible for transporting nuclear-encoded proteins into mitochondria. Additionally, mitochondrial calcium signaling is facilitated by calcium uptake into the mitochondrial matrix by the calcium uniporter (CaU) in response to intracellular calcium fluctuation. Furthermore, mitochondria play an important role in the apoptosis process. When apoptotic signals are received, the OMM is compromised, resulting in OMM permeabilization (MOMP) and the release of cytochrome c (Cyt-c) and other pro-apoptotic proteins from the intermembrane space into the cytosol, causing apoptotic cell death.

Fig. (3)

The role of mitochondrial dysfunction in AD etiology. Aβ and tau are known to cause mitochondrial dysfunction, resulting in the modulation of many other variables. ROS production results in the formation of lipid peroxidation and DNA damage, triggering apoptosis. The activation of mitochondrial permeability transition pores (mPTPs) results in damaged mitochondria with decreased ΔΨm, causing the release of Cyt-c and apoptosis-inducing factor (AIF) and the induction of the apoptosis pathway. The antioxidants Aβ and pTau enhance mitochondrial fission and mitophagy.

Fig. (4)

Phytochemicals are emerging as potential treatments for mitochondrial dysfunction in AD development. Abnormal APP is digested by the β- and γ-secretases, resulting in the buildup of extracellular Aβ. When there is insufficient clearance of Aβ or Aβ production, aggregation occurs, resulting in the buildup of diverse Aβ assembly types. Aβ accumulation is directly associated with mitochondria, and ROS production is directly associated with other intracellular pathways. Neurological degeneration and synaptic function dysregulation in brain regions implicated in learning and memory impairment in AD are caused by these oxidative stress reactions, which have a multifactorial mechanism of action, in addition to neurological degeneration and synaptic dysregulation function.

Fig. (5)

Mitophagy mechanism in AD pathogenesis. Parkin ubiquitylates various OMM elements, which are then identified by the adaptor proteins optineurin (OPTN), p62, nuclear dot protein 52 kDa (NDP52), and NBR1 autophagy cargo receptor (NBR1), recruiting the damaged mitochondria to the autophagy process and triggering autophagosome production via interactions with LC3. Additionally, MMP, toxic chemicals, mitochondrial ROS (mtROS), heat, and neuroinflammation are keys factor in initiating mitochondrial-mediated autophagy, damaging neuronal cells.

Fig. (6)

NP-based drug delivery systems for treating AD. NPs can bypass biological barriers, and their use in precision medicine applications may benefit AD treatment. NP designs that increase delivery can potentially improve the performance of precision medicine and the speed at which clinical trials are conducted for AD drugs.