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Fig. 1 | Journal of Neuroinflammation

Fig. 1

From: Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

Fig. 1

The pathogenic hallmarks of AD in the human brain over time. In the earliest stages of AD, the formation of Aβ occurs due to abnormal cleavage of amyloid precursor protein (APP) by β- and γ-secretases, whereas it is normally cleaved by α- and γ-secretases. Aβ monomers are intrinsically disordered and have a propensity to oligomerize and aggregate into Aβ plaques. Aβ activates microglia and astrocytes, causing them to clear Aβ via phagocytosis and proteolysis. The presence of Aβ has also been linked to the hyperphosphorylation and destabilization of tau and the subsequent formation of tau tangles. Inflammatory activation and signaling can also cause further production of Aβ. Tau pathology is observed approximately 10 years after the initiation of Aβ aggregation. Tau is a microtubule-associated protein that is predominately found in neurons, where it is regulated by phosphorylation and other post-translational modifications (i.e., acetylation, ubiquitylation) to stabilize microtubules, regulate axonal stability, and maintain cell function. While tau contains 2–3 mol of phosphate in the healthy brain, it can accumulate up to three times more phosphate in AD. This hyperphosphorylation lowers the affinity of tau for the microtubules, increases its resistance to degradation by proteases and the proteasome, and leads to its fibrillization and aggregation into neurofibrillary tangles, which ultimately causes neuronal loss and cognitive decline. The increase in Aβ aggregation, inflammation, and tau hyperphosphorylation leads to a variety of downstream effects on neuronal synapses, including inhibition of LTP, impaired dendritic trafficking, increased excitotoxicity, and a reduction in synaptic density. This leads to synaptic loss and eventual neuronal loss approximately 20 years following initial disease pathogenesis, which is followed by the symptomatic cognitive decline

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