Figure 1 | Scientific Reports

Figure 1

From: A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer’s disease mouse model

Figure 1

ApoE4 and SirT1 pathways. ApoE4 exacerbates AD-related pathology by increasing β pathway processing of full-length amyloid precursor protein (APP) and therefore Aβ production; and by decreasing astrocyte- and microglia-mediated Aβ clearance. ApoE4 expression is also associated with mitochondrial dysfunction and lysosomal leakage in AD. A reduction of SirT1 as a result of ApoE4 expression may be a major contributor to the deleterious effects of ApoE4 because this can lead to a decrease in the FOXO3-mediated antioxidant response, PGC1α-mediated radical oxygen species (ROS) sequestration, and ADAM10 expression. Decreases in SirT1 also increase p53-mediated apoptosis, NFκB-mediated Aβ toxicity, and acetylation of tau; all of which exacerbate AD pathology.

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