An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most prominent neurodegenerative disorder in the aging population. It is characterized by cognitive decline, gradual neurodegeneration, and the development of amyloid-β (Aβ)-plaques and neurofibrillary tangles, which constitute hyperphosphorylated tau. The early stages of neurodegeneration in AD include the loss of neurons, followed by synaptic impairment. Since the discovery of AD, substantial factual research has surfaced that outlines the disease's causes, molecular mechanisms, and prospective therapeutics, but a successful cure for the disease has not yet been discovered. This may be attributed to the complicated pathogenesis of AD, the absence of a well-defined molecular mechanism, and the constrained diagnostic resources and treatment options. To address the aforementioned challenges, extensive disease modeling is essential to fully comprehend the underlying mechanisms of AD, making it easier to design and develop effective treatment strategies. Emerging evidence over the past few decades supports the critical role of Aβ and tau in AD pathogenesis and the participation of glial cells in different molecular and cellular pathways. This review extensively discusses the current understanding concerning Aβ- and tau-associated molecular mechanisms and glial dysfunction in AD. Moreover, the critical risk factors associated with AD including genetics, aging, environmental variables, lifestyle habits, medical conditions, viral/bacterial infections, and psychiatric factors have been summarized. The present study will entice researchers to more thoroughly comprehend and explore the current status of the molecular mechanism of AD, which may assist in AD drug development in the forthcoming era.

Keywords: Alzheimer’s disease; amyloid plaques; molecular mechanism; risk factors; tau tangles.

Figure 1

Amyloidogenic pathway in the pathogenesis of Alzheimer’s disease showing the formation of amyloid plaques. Within the membrane, β-secretase cleaves APP in the first instance, followed by γ-secretase. The extracellular amyloid-β that is released by the proteolytic breakdown of APP via the amyloidogenic pathway is susceptible to self-aggregation, resulting in the development of cytotoxic oligomers and insoluble Aβ fibrils/plaques.

Figure 2

Systematic illustration of the amyloid-β hypothesis in Alzheimer’s disease. (A) APP processing to form Aβ, which simultaneously assembles as aggregates of the Aβ oligomer (oAβ) and form amyloid plaques. (B) Aβ-associated synaptic dysfunction by the impairment of LTP and LTD. Aβ receptors including NMDAR, PrPc, EphA4, EphB2 & LiLRB2 have been shown to induce synaptotoxicity by interaction with Aβ. EphA4-associated synaptic and cognitive malfunction may be inhibited by SORLA. Fyn kinase functions as an essential control mechanism for NMDAR related oAβ neurotoxicity. oAβ halts the normal mitochondrial function, which results in activated capsase-3, upregulated ROS, and decrease in ATP. This further worsens the synaptic dysfunction.

Figure 3

Systematic illustration for Aβ-mediated glial response in AD. (A) oAβ might activate microglia by binding to different Aβ receptors including TLR4, RAGE, LRP1, CD36, and specifically to TREM2, which stimulates the SYK pathway via DAP12 inducing Aβ degeneration. (B) Aβ dependent astrocyte dysfunction by enhanced interactions between Aβ/APOPE and LRP1 results in astrocyte activation by releasing TNF-α, IL-1β, IL-6, and IL-8. Furthermore, oAβ is also capable of direct astrocyte activation by AQP4, CD36, α7-nAchR, CD47, and CaSR. This astrocyte activation leads to neuronal damage through TNF-α, IL-1β, IL-6, and excitotoxication/irregulated homeostasis of glutamate.

Figure 4

An illustration of the mitochondrial dysfunction and oxidative stress in the pathogenesis of AD. (A) Multiple age-related processes, mutations, and toxic fluctuations such as metal exposure can all adversely affect mitochondria. Mitochondrial dysfunction further results in bioenergetic deficits, calcium imbalance, and free radical production. This causes oxidative stress, which exacerbates mitochondrial impairment, synaptic malfunction, cognitive decline, and memory loss. (B) The cellular redox equilibrium is disrupted by ROS generation or a compromised antioxidant arrangement, which leads to an oxidative imbalance and excessive ROS output. By adversely influencing mitochondrial energy reserves, disrupting energy metabolic processes, and impairing dynamics and mitophagy, elevated ROS reduces mitochondrial ΔΨm and ATP production. Caspase activity also rises as a result of ROS, which additionally starts the apoptotic process. However, excessive ROS generation inhibits phosphatase 2A (PP2A), which leads to glycogen synthase kinase 3 (GSK3) activation. This results in tau hyperphosphorylation and NFT buildup. (C) The functions of the mitochondria that are extensively hampered in AD have been highlighted.

Figure 5

Systematic illustration for tau pathogenesis in AD. (A) Tau aggregation and oligomer formation result in mitochondria fragmentation and the impairment of vesicle mobility/release, which causes presynaptic dysfunction. (B) Truncated and hyperphosphorylated tau species enter the post-synapse and modulate NMDAR/Fyn complexes, leading to LTP impairment. By means of the heparan sulfate proteoglycans (HSPGs)-mediated route, extracellular pathogenic tau species may be embodied in neurons, causing intracellular tau accumulation. (C) Extracellular tau interacts with CX3CR1, enters the microglia, and degrades. Microglial NF-κB and NLRP3 inflammasome pathways are activated by tau, which allows for the release of pro-inflammatory cytokines. These cytokines enhance the CDK5 and P38 activity, which leads to increased hyperphosphorylation.

Figure 6

Different risk factors attributed to AD development.