Examination of Longitudinal Alterations in Alzheimer’s Disease-Related Neurogenesis in an APP/PS1 Transgenic Mouse Model, and the Effects of P33, a Putative Neuroprotective Agent Thereon

Abstract

Neurogenesis plays a crucial role in cognitive processes. During aging and in Alzheimer’s disease (AD), altered neurogenesis and neuroinflammation are evident both in C57BL/6J, APPSwe/PS1dE9 (Tg) mice and humans. AD pathology may slow down upon drug treatment, for example, in a previous study of our group P33, a putative neuroprotective agent was found to exert advantageous effects on the elevated levels of APP, Aβ, and neuroinflammation. In the present study, we aimed to examine longitudinal alterations in neurogenesis, neuroinflammation and AD pathology in a transgenic (Tg) mouse model, and assessed the putative beneficial effects of long-term P33 treatment on AD-specific neurological alterations. Hippocampal cell proliferation and differentiation were significantly reduced between 8 and 12 months of age. Regarding neuroinflammation, significantly elevated astrogliosis and microglial activation were observed in 6- to 7-month-old Tg animals. The amounts of the molecules involved in the amyloidogenic pathway were altered from 4 months of age in Tg animals. P33-treatment led to significantly increased neurogenesis in 9-month-old animals. Our data support the hypothesis that altered neurogenesis may be a consequence of AD pathology. Based on our findings in the transgenic animal model, early pharmacological treatment before the manifestation of AD symptoms might ameliorate neurological decline.

Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aβ pathology

“…It is known that multiple peptide products, in addition to Aβ 1-42 , are elevated as a result of elevated APP processing in APP/PS1 mice (Szögi et al, 2022 ). To establish the causality between Aβ 1-42 and seizure response, we unilaterally injected synthetic Aβ 1-42 peptides or a scrambled (Scr) peptide (1.25 µM, 4 µl) into the ventricle of WT mice at 7 weeks of age.…”

Aberrant accumulation of age- and disease-associated factors following neural probe implantation in a mouse model of Alzheimer’s disease

“…Despite a visible difference in the density of neurons within the 0-50 μm tissue region around chronically implanted microelectrodes at 1-and 16-weeks post-implantation, we did not detect any significant differences between WT and APP/PS1 mice. It is important to keep in mind that at 16-weeks post-implantation APP/PS1 mice are at 6 months of age and neuronal numbers are not expected to be naturally altered within the AD model at this age [46][47][48] . Furthermore, our analyses are only limited to understanding whether NeuN+ neurons are present or not around the electrode compared to intact control regions but does not discern whether the neurons that remain are viable or whether they may be otherwise functionally impaired around chronically implanted devices.…”

Aberrant accumulation of age- and disease-associated factors following neural probe implantation in a mouse model of Alzheimer’s disease

“…Despite a visible difference in the density of neurons within the 0-50 µm tissue region around chronically implanted microelectrodes at 1 and 16 weeks post-implantation, we did not detect any significant differences between WT and APP/PS1 mice. It is important to keep in mind that at 16-weeks post-implantation APP/PS1 mice are at 6 months of age and neuronal numbers are not expected to be naturally altered within the AD model at this age [58][59][60]. Furthermore, our analyses are only limited to understanding whether NeuN+ neurons are present or not around the electrode compared to intact control regions but does not discern whether the neurons that remain are viable or whether they may be otherwise functionally impaired around chronically implanted devices.…”