The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer's Disease: Therapeutic Implications and Future Perspectives

Abstract

Alzheimer's disease (AD), the most common form of dementia, has increasing incidence, increasing mortality rates, and poses a huge burden on healthcare. None of the currently approved drugs for the treatment of AD influence disease progression. Many clinical trials aiming at inhibiting amyloid plaque formation, increasing amyloid beta clearance, or inhibiting neurofibrillary tangle pathology yielded inconclusive results or failed. Meanwhile, research has identified many interlinked vicious cascades implicating oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, and has pointed to novel therapeutic targets such as improving mitochondrial bioenergetics and quality control, diminishing oxidative stress, or modulating the neuroinflammatory pathways. Many novel molecules tested in vitro or in animal models have proven efficient, but their translation into clinic needs further research regarding appropriate doses, delivery routes, and possible side effects. Cell-based therapies and extracellular vesicle-mediated delivery of messenger RNAs and microRNAs seem also promising strategies allowing to target specific signaling pathways, but need further research regarding the most appropriate harvesting and culture methods as well as control of the possible tumorigenic side effects. The rapidly developing area of nanotechnology could improve drug delivery and also be used in early diagnosis.

Keywords: Alzheimer’s disease; antioxidants; mitochondrial dysfunction; nanotechnology; neuroinflammation; oxidative stress; stem cell therapies.

Figure 1

PINK1 accumulates on the OMM of damaged mitochondria, followed by recruitment and phosphorylation of Parkin which ubiquitinates OMM proteins such as the translocase of the outer mitochondrial membrane 20 (TOM20) and mitofusins (Mfn1 and Mfn2). The pre-initiation complex containing ULK1 (Unc 51-like kinase 1), Atg (autophagy related proteins) 13 and 101 and FIP200 (focal adhesion kinase family interacting partner 200) is activated, followed by recruitment of phosphatidyl inositide 3 kinase (PI3K), Atg14, beclin 1, AMBRA1 (autophagy and beclin 1 regulator 1), vascular sorting proteins Vsp34 and 15, and LC3 (light chain 3) leading to generation of phosphatidyl inositol-3-phosphate (PI3P). The ubiquitinated OMM proteins recruit autophagy adaptor proteins (NRB1—neighbor of BRCA1 gene 1 protein, optineurin, TAX1BP1—Tax 1 binding protein 1, NDP52—nuclear dot protein 52, p62), which interact with LC3 leading to closure of the of the phagophore and formation of the autophagosome. Rab7, a lysosome-associated small GTPase, LRRK2 (leucine rich repeat kinase 2) and LAMP2 (lysosome-associated membrane protein 2) mediate fusion of the autophagosomes with lysosomes. In AD, Aβ can be internalized by mitochondria via TOM, damaging the organelle, while cytoplasmic Aβ decreases the levels of PINK1 and parkin, thereby impairing the mitophagy pathway.

Figure 2

TNF signaling in Alzheimer’s disease. TNF receptor 1 (TNFR1) contains an intracellular TNF-receptor associated death domain (TRADD), which, upon TNF binding associates to FAS-associated death domain (FADD) and activates caspase 8 and caspase 3 leading to apoptosis. TNF receptor 2 (TNFR2) interacts with TNF receptor-associated factors (TRAF1, TRAF2, TRAF3) which interact with cellular inhibitor of apoptosis proteins 1 and 2 (CIAP1/2), NF-κB-inducing kinase (NIK) and phosphoinositide 3-kinase (PI3K), promoting cell survival. Akt—serine-threonine kinase; IκB—inhibitor of kappa B; IKK3—IκB kinase 3; NF-κB—nuclear factor kappa B; RIP—receptor interacting protein; MKK—mitogen-activated protein kinase; MAPKs—phosphorylated mitogen-activated kinases;. In AD, Aβ can physically interact with TNFR1 and promote neuronal death, while the caspases activated by TNFR1 signaling can cleave amyloid precursor protein (APP), increasing the Aβ load in a feed-forward loop.

Figure 3

A complex relationship exists between oxidative stress which leads to mitochondrial dysfunction, that compromises mitochondrial bioenergetics and further increases oxidative stress. ROS also lead to protein misfolding and impair proteasomal function, causing accumulation of misfolded proteins and Aβ, which augments mitochondrial dysfunction. Through impaired enzymatic activity, various signaling pathways are altered, causing tau hyperphosphorylation. In addition, ROS activate microglia and neuroinflammation that further augments oxidative stress in AD.