Figure 4.

The pathogenesis of AD involving Aβ-induced toxicity via increased ROS and dysregulation of intracellular calcium as well as altered neurogenesis due to imbalance between positive regulation of neurogenesis by sAPPα and negative regulation of neurogensis by AICD. β- and γ-secretases cleavage of APP could produce Aβ. The oligomerization and fibrillization of Aβ could lead to formation of Aβ plaque, leading to increased ROS and dysruption of intracellular calcium. The γ-secretases, presenilins, can function as ER calcium leak channels, which could aggravate the increased intracellular calcium due to Aβ accumulation. The ROS and dysregulation of intracellular calcium could contribute to neuron demise. On the other hand, the α-secretases cleavage of APP could lead to sAPPα formation. The sAPPα can function on secreted cell itself or nearby cells via autocrine or paracrine mechanisms. The sAPPα can promote neurogenesis via so far unknown mechanisms. Furthermore the sAPPα can function to promote neurons survival, which could counter against neuron demise induced by Aβ accumulation. The γ-secretase cleavage of APP can produce AICD fragments. The AICD can bind with Fe65 and form complex, which can enter nucleus and function to negatively regulate neurogenesis via unknown mechanisms. Pathological factors which disruption the balance between positive regulation of neurogenesis by sAPPα and negative regulation of neurogenesis by AICD will lead to decreased neurogenesis, increased neuron demise and cooperate with Aβ plaque induced toxicity to contribute to AD.