Fig. 10

Mechanisms underlying AIE-induced hippocampal pathology. Progenitor cells in the subgranular zone of the hippocampus go through a multiweek maturation where they (1) proliferate and (2) differentiate and develop into immature neurons, during which they functionally integrate within hippocampal circuitry. Damaged or otherwise deficient cells do not survive this process, and activation of cell-apoptotic pathways is an important normal physiological checkpoint (3). However, AIE increases cell death beyond normal apoptotic levels (3), as evidenced by increases in immunoreactivity of cleaved Casp3 in immature neurons. While these neuroimmune changes are persistent despite abstinence, they are not permanent and can be prevented and reversed by pharmacological intervention with galantamine. More specifically, galantamine rescues AIE-induced deficits in hippocampal neurogenesis (2) by driving increases in cell proliferation (1) and preventing overactivation of cell death pathways in newborn neurons (3). AIE-induced proinflammatory cascades is a critical mechanism underlying AIE-induced neurogenic deficits as increased proinflammatory signaling upsets the environmental milieu necessary for healthy levels of hippocampal neurogenesis. Specifically, AIE increases HMGB1 expression, which we have previously shown activates RAGE and TLR4 receptors (as reviewed by [47]). RAGE and TLR4 signaling cascades induce phosphorylation of the transcription factors NF-ĸB and AP-1, ultimately resulting in downstream induction of other proinflammatory signaling, including COX-2. Conversely, the chemokine CCL2 is expressed in the hilus and released as a neuromodulator to activate CCR2 receptors. CCR2 receptors are expressed in the subgranular zone of the dentate where they have also been shown to influence downstream proinflammatory cascades including NF-ĸB and AP-1 phosphorylation and COX-2 signaling. These pathways create a network of positive feedback for proinflammatory signaling cascades after AIE, which are prevented and restored by galantamine