Disruption of neurogenesis by amyloid β‐peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease

Abstract

Neurogenesis occurs in the adult mammalian brain and may play roles in learning and memory processes and recovery from injury, suggesting that abnormalities in neural progenitor cells (NPC) might contribute to the pathogenesis of disorders of learning and memory in humans. The objectives of this study were to determine whether NPC proliferation, survival and neuronal differentiation are impaired in a transgenic mouse model of Alzheimer's disease (AD), and to determine the effects of the pathogenic form of amyloid b-peptide (Ab) on the survival and neuronal differentiation of cultured NPC. The proliferation and survival of NPC in the dentate gyrus of the hippocampus was reduced in mice transgenic for a mutated form of amyloid precursor protein 2 that causes early onset familial AD. Ab impaired the proliferation and neuronal differentiation of cultured human and rodent NPC, and promoted apoptosis of neuron-restricted NPC by a mechanism involving dysregulation of cellular calcium homeostasis and the activation of calpains and caspases. Adverse effects of Ab on NPC may contribute to the depletion of neurons and cognitive impairment in AD.

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

“…Microglial cells recruited to the injury site showed elevated increased P2X7 receptor expression, as observed in animal models and human patients [83,84]. P2X7 receptor activation by elevated ATP concentration promotes the secretion of the cytokines by microglial cells and activated oxygen species, increasing inflammation and stimulating Aβ-plaque formation, which also stimulates ATP liberation [82,85,86]. Furthermore, the P2Y1 subtype is expressed in AD typical structures such as Aβ plaques and neurofibrillary tangles, and receptor immunostaining was notably high in AD brain suggesting that P2Y1 receptors may participate in signaling events triggering neurodegenerative processes [61,81,82].…”

Adult neurogenesis is functionally associated with AD-like neurodegeneration

“…It should be noted that one consistent finding in those models is that the deposition of Aβ is dramatically increased in the brain. There is evidence that the deposition of Aβ itself may disrupt neurogenesis (Haughey, et al, 2002, Zhang, et al, 2007. Therefore, it might be possible that the changes in neurogenesis were, at least partially, dependent on the amount of Aβ deposition.…”

Neural stem cells: mechanisms and modeling

“…The enriched environment (EE)-induced proliferation and neuronal differentiation of hippocampal progenitor cells in mice harboring the FAD-linked human PS1 variant transgenes (PS1ΔE9 or PS1M146L) was significantly impaired, which appeared to involve soluble factors released from microglia (Choi et al, 2008). Similarly, the proliferation and survival of neural progenitor cells were reduced in transgenic mice expressing a mutated form of APP (APPswe) that causes early-onset FAD (Haughey et al, 2002). An agedependent decrease in SGZ proliferation was also observed in mice transgenic for human V717F mutant APP, a model of AD with age-dependent accumulation of Aβ42-containing plaques (Donovan et al, 2006).…”