Presence of inflammatory cytokines from activated microglia and astrocytes, no cost radicals, and oxidative pressure (Kaur et al., 2019; Ozben and Ozben, 2019; Poudel and Park, 2022).The primary PATHOGENESIS OF ALZHEIMER’S DISEASEThe accumulation of a is among the principal causes of AD neurodegeneration. A accumulates in the neocortex region with the orbital frontal cortex, temporal lobe and basal cortex, and steadily spreads into the entire neocortex, hippocampus, amygdala, diencephalon and basal ganglia. In serious circumstances, A also entails the middle brain, the inferior brainstem plus the cerebellum cortex. A originates in the sequential cleavage of amyloid precursor protein (APP). Cleavage by -secretase inside of the luminal/extracellular domain generates -carboxylterminal fragments. Following -secretase cleavage, -secretase processes APP on the carboxyl terminus to provide A (Huat et al., 2019). These insoluble A fibrils accumulate and spread towards the synaptic gap, which interferes with synaptic signal conduction (Rabbito et al., 2020; Wang et al., 2020), resulting in the formation of insoluble plaques. This polymerization also prospects to kinase activation, resulting in hyperphosphorylation on the tau proteins that are involved in microtubule stabilization. This leads towards the dissociation of microtubules and axonal transport dysfunction (Dixit et al., 2008; Zhang et al., 2021), which can make tau protein steadily collect to form NFT, leading to abnormal communication and signal conduction of neurons, and eventually apoptosis of neurons (Sung et al., 2020; Dregni et al., 2022). Right after the formation of plaques and fiber tangles, microglia andMicrogliaMicroglia show both valuable and damaging effects in AD. Around the a single hand, activated microglia lessen the deposition of a by phagocytosis (Frautschy et al., 1998; Yamamoto et al., 2018), secrete neurotrophic aspects, and encourage the survival of neurons and tissue repair (Gehrmann et al., 1995; Liu and Hong, 2003). On the flip side, the improve of nearby cytokine concentration in AD individuals brings about the downregulation of a phagocytic receptor expression in microglia, resulting in the accumulation of a and also the lessen of a clearance charge. On top of that, the tolllike receptor (TLR) on microglia is activated, resulting in theFrontiers in Aging Neuroscience www.frontiersin.orgJune 2022 Volume 14 D1 Receptor Inhibitor drug ArticleWeng et al.Exosomes in Alzheimer’s Diseaseactivation of microglia and the secretion of pro-inflammatory cytokines and chemokines (Heneka et al., 2015). This overactivation ordinarily happens beneath continual ailments, which not simply creates pro-inflammatory mediators and cytotoxicity but additionally prospects to the prolongation of neuroinflammation. The steady formation of a, irritation, and activated microglia kind a beneficial suggestions circuit, aggravating the severity of AD (Hickman et al., 2008; Hansen et al., 2018; Prinz et al., 2019). In addition, reactive microglia gather about the cells forming NFT, indicating that tau protein phosphorylation can be connected to inflammatory response (Azevedo et al., 2013). A Calcium Channel Inhibitor review number of studies have proven that continual amounts of inflammatory mediators aggravate the activation of key protein kinases that handle tau phosphorylation (Azevedo et al., 2013; Ahmad et al., 2022). One example is, long-term release of tumor necrosis element (TNF-) from microglia continues to be proven to induce tau aggregation in neurons in vitro (Azevedo et al., 2013; Heneka et al., 2015; Ahmad et al., 2022).and Morillas-Ruiz, 2012;.