Cellular and Molecular Mechanisms Governing Functional Recovery of Dementia Mice after Neuronal cell Transplantation

Massive degeneration of the basal forebrain cholinergic cells is one of the major histopathological changes of Alzheimer's disease (AD). The degeneration leads to Acetylcholine (ACh) deficits in the cortex and hippocampus. AD disease severity was negatively correlated with ACh expression. We conducted neuronal transplantation with cells derived from Human Induced Pluripotent Stem (hiPS) cells into the bilateral hippocampi of human amyloid precursor protein transgenic AD mice. The transplantation significantly improved cognitive dysfunction in the mice. Transplanted neurons differentiated further in the host cortex into human Choline Acetyl Transferase (ChAT)+ cholinergic neurons. In the hippocampus, the grafted cells preferentially differentiated into human vesicular GABA transporter (VGAT)+ cells. We suggest that transplanted neurons may compensate for neurotransmitter loss associated with AD lesions. In this review, we summarize current topics of neurotransmitter system perturbation of AD pathology. We would like to emphasize the importance of GABA/GABA receptor (GABAR) circuits as well as ACh/ACh receptor (AChR) pathways in the hippocampus reconstituted by the transplantation.