Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Abstract

Our previous analyses showed that allopregnanolone (APα) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APα to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between APα-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells. Learning and memory function was assessed using the hippocampal-dependent trace eye-blink conditioning paradigm. At 3 months, basal level of BrdU+ cells in the SGZ of 3xTgAD mice was significantly lower relative to non-Tg mice, despite the lack of evident AD pathology. APα significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude. As with the deficit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. APα reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APα-induced survival of neural progenitors was significantly correlated with APα-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Aβ, may contribute to the cognitive phenotype of AD, and that APα could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.

FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders

“…neurogenesis (BrdU + cell count) in the SGZ and improved memory performance (53). Taken together, these studies strongly support the therapeutic potential of the enhancement of neurogenesis at the SGZ of the dentate gyrus in AD brains.…”

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

“…Although some previous reports show that functional neurogenesis is reduced in the 3xTgAD mouse models of AD (86,87), the increased proliferation reported here is consistent with data obtained either by DCX positive alone or by DCX/BrdU cell counts in a transgenic mouse model expressing human APP isoforms with the Swedish (K670N/M671L) and Indiana (V717F) mutations (88) and in other models (APP/PS1 double transgenic) (89). Interestingly, a similar increase in adult hippocampal cell proliferation (measured by multiple endogenous newborn neuron markers) was found in the subgranular zone of human subjects with AD (88).…”

“…Interestingly, such interventions including drugs, enriched environment, and exercise, which all increase neurogenesis, has also been shown to improve the learning and memory deficits in AD mice models and aged rodents (86,(92)(93)(94). Furthermore, treatments that decrease neurogenesis negatively impact both learning and memory (95), and the level of neurogenesis has been shown to correlate with cognitive function in both rodents (86,91,96) and humans (97), Thus it is clear that newborn neurons studies with endogenous DCX expression and other such markers play important roles in learning and memory. Several explanations have been put forward including the fact that adult-born neurons have a lower threshold for induction of long-term potentiation (95) and immediate early gene expression compared with the matured dentate-gyrus neurons.…”

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

“…DHP and THP, which are reported to have beneficial effects on the brain [46,47]. The two enzymes responsible for the conversion of PROG to DHP and, subsequently, to THP, i.e.…”