Figure 2.

Microenvironmental changes interact with intrinsic cellular alterations to promote the selective vulnerability of entorhinal layer II neurons in aging and AD. Neurons located further away from plaques are likely to maintain a greater degree of structural and functional integrity in AD, while neurons situated close to plaques and in the vicinity of the vasculature are exposed to elevated levels of inflammatory cytokines such as tumor-necrosis factor-alpha (TNF alpha) and monocyte chemoattractant protein 1 (MCP1). Proinflammatory alterations in the local microenvironment, together with intrinsic changes in neuronal reelin (Reln), brain-derived neurotrophic factor (BDNF), and tissue inhibitor of metalloproteinase 3 (TIMP3) expression, could potentially impair synaptic function. This impairment would alter signal propagation both locally, through reductions in NMDA NR1 subunit and muscarinic acetylcholine receptor M1 (mAChR1) expression, and downstream in the hippocampus, through reductions in synaptophysin expression in the terminal fields for layer II entorhinal neurons.