Abstract
Alzheimer’s disease (AD) is a devastating neurological disorder characterized by progressive memory loss and cognitive decline. Histopathologically, AD is characterized by two types of protein aggregates in brain, amyloid- (A) plaques and tau-containing neurofibrillary tangles, as well as by massive synaptic loss and neuron death. Aβ peptides act upstream of tau in AD pathogenesis, and have been demonstrated to interact with multiple proteins at the cell surface. In particular, Aβ oligomers (AβOs) have been shown to interact with and cause calcium influx thorough the N-methyl-D-aspartate receptor. Neurons in adult brain are normally in a permanently post-mitotic state, but in AD they exhibit ectopic cell cycle re-entry (CCR), which leads to their eventual death.
The data presented in the following dissertation demonstrates that A-mediated calcium influx through NMDAR is necessary for the induction of CCR in neurons, connecting the calcium dysfunction in AD to the CCR pathway of neuron death. Chelating total intracellular calcium in neurons with BAPTA-AM treatment inhibits CCR, indicating CCR is calcium dependent. When primary neurons are treated with the pharmacological inhibitor MK-801, specifically blocking calcium influx through the NMDAR channel pore, CCR is also inhibited, implying a critical role for NMDAR calcium influx in CCR pathogenesis. Additionally, AO treatment causes early activation of CaMKII, a calcium-dependent protein kinase that must phosphorylate tau at Ser416 for CCR to occur. Blocking NMDAR-mediated calcium influx by MK-801 treatment blocks this CaMKII activation, putting NMDAR upstream of both CaMKII activation and subsequent phosphorylation of tau. Treatment of primary neurons with memantine, an FDA approved drug for the treatment of moderate to severe AD that blocks NMDAR calcium influx, also inhibits CCR. Furthermore, treatment of the AD mouse model Tg2576 with memantine before the onset of AD pathology inhibits CCR in these mice, suggesting that memantine has a previously undemonstrated prophylactic role in AD treatment.
Together, these results indicate that excess calcium influx via the NMDA receptor is an essential early step in AO-induced neuronal CCR. Furthermore, the collective data imply that this specific type of calcium dysregulation triggers the two cell biological responses that together account for the behavioral deficits in AD: excitotoxicity at the synapse, and neuron death (via CCR).
