Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a major contributor of dementia leading to the degeneration of neurons in the brain with major symptoms like loss of memory and learning. Many evidences suggest the involvement of neuroinflammation in the pathology of AD. Cytokines including TNF-α and IL-6 are also found increasing the BACE1 activity and expression of NFκB resulting in generation of Aβ in AD brain. Following the interaction of Aβ with microglia and astrocytes, other inflammatory molecules also get translocated to the site of inflammation by chemotaxis and exaggerate neuroinflammation. Various pathways like NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide and COX trigger microglia to release inflammatory cytokines. PPARγ agonists like pioglitazone increases the phagocytosis of Aβ and reduces inflammatory cytokine IL-1β. Celecoxib and roficoxib like selective COX-2 inhibitors also ameliorate neuroinflammation. Non-selective COX inhibitor indomethacin is also potent inhibitor of inflammatory mediators released from microglia. Mitophagy process is considered quite helpful in reducing inflammation due to microglia as it promotes the phagocytosis of over activated microglial cells and other inflammatory cells. Mitophagy induction is also beneficial in the removal of damaged mitochondria and reduction of infiltration of inflammatory molecules at the site of accumulation of the damaged mitochondria. Targeting these pathways and eventually ameliorating the activation of microglia can mitigate neuroinflammation and come out as a better therapeutic option for the treatment of Alzheimer's disease.

Keywords: Alzheimer’s disease; Molecular pathways; Neuroinflammation; Therapeutics.

Fig. 1

Pathophysiology of Alzheimer’s disease. Figure 1 depicts the multiple factors responsible for the progression of Alzheimer’s disease. Amyloid plaques and hyperphosphorylated tau are the major ones. Extracellular amyloid β deposition leads to the generation of senile plaques. Hyperphosphorylated tau leads to the disassembly of microtubules and damages the cytoskeleton and signal transduction processes in neuronal cells. Other factors like neuroinflammation, oxidative stress, cholinergic insufficiency, mitochondrial dysfunction and autophagy dysfunction also play major role in the disease progression

Fig. 2

Neuroinflammation in Alzheimer’s disease. Figure 2 shows the hyperactive glial cells including astrocytes and microglia upon interaction between Aβ and tau. Microglia and astrocytes are the major cells in the brain responsible for inflammatory responses. Due to the activation of glial cells various pro-inflammatory mediators are released which direct more inflammatory molecules at the site of injury leading to exaggerated inflammatory response in brain called neuroinflammation

Fig. 3

Neuroinflammatory pathways and drugs targeting neuroinflammation. Figure 3 shows that due to dysregulation of various pathways in brain and periphery leads to hyperactivation of Glial cells and other inflammatory cells in the brain which contributes to neuroinflammatory pathway of AD. Drugs like PPARγ agonists, COX inhibitors, vitamin E, vitamin C, curcumin and catechin act via various mechanisms to reduce the neuroinflammatory pathways thus prevent the progression of AD