Transgenic Mice with Chronic NGF Deprivation and Alzheimer's Disease-Like Pathology Display Hippocampal Region-Specific Impairments in Short- and Long-Term Plasticities

Erythropoietin (EPO) promotes neurogenesis and neuroprotection. We here compared the protection induced by two EPO formulations in a rodent model of Alzheimer’s disease (AD): rHu-EPO and a low sialic form, Neuro-EPO. We used the intracerebroventricular administration of aggregated Aβ25-35 peptide, a non-transgenic AD model. rHu-EPO was tested at 125–500 µg/kg intraperitoneally and Neuro-EPO at 62–250 µg/kg intranasally (IN). Behavioural procedures included spontaneous alternation, passive avoidance, water-maze and object recognition, to address spatial and non-spatial, short- and long-term memories. Biochemical markers of Aβ25-35 toxicity in the mouse hippocampus were examined and cell loss in the CA1 layer was determined. rHu-EPO and Neuro-EPO led to a significant prevention of Aβ25-35-induced learning deficits. Both EPO formulations prevented the induction of lipid peroxidation in the hippocampus, showing an antioxidant activity. rHu-EPO (250 µg/kg) or Neuro-EPO (125 µg/kg) prevented the Aβ25-35-induced increase in Bax level, TNFα and IL-1β production and decrease in Akt activation. A significant prevention of the Aβ25-35-induced cell loss in CA1 was also observed. EPO is neuroprotective in the Aβ25-35 AD model, confirming its potential as an endogenous neuroprotection system that could be boosted for therapeutic efficacy. We here identified a new IN formulation of EPO showing high neuroprotective activity. Considering its efficacy, ease and safety, IN Neuro-EPO is a new promising therapeutic agent in AD.

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PM2.5 can Promote the Alzheimer's Disease-like Changes through Microglia Related Mechanism in Mice

10.21203/rs.3.rs-90903/v1 ◽

2020 ◽

Author(s):

Jiaqi Wang ◽

Jie Li ◽

Jia Wang ◽

Wenping Sun ◽

Qiuyuan Fang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Complete Blood Count ◽

Morphological Changes ◽

Mrna Level ◽

Air Pollutant ◽

Whole Genome ◽

Expression Of Genes

Abstract Background: PM2.5, the main particulate air pollutant, poses serious hazard to human health. Alzheimer's disease (AD) is a major neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles. Recent studies reported that PM could promote AD-like pathologies in human brain. However, the mechanism of PM2.5-induced AD-like changes is still unclear and more investigations are needed for further understanding.Methods: In this study, we established experimental model of long-term PM2.5 exposure with young/old wildtype C57BL/6 and APP/PS transgenic mice. Behavior assessments were monitored after four weeks of exposure. The changes of blood cells were detected by Complete Blood Count and splenic macrophages were detected by flow cytometry. Immunohistochemical staining was used to observe the damage of PM2.5 on neurons, the deposition of Aβ and the changes of microglia. RNA-seq was used to analyze the whole genome changes of hippocampus after PM2.5 exposure. In addition, microglia related genes were analyzed via Real-time PCR. Results: After mice were exposed to PM2.5 for a month, some AD-like behavioral changes, such as learning and memory impairment were detected especially in old and transgenic mice. The histopathological changes, such as β-amyloid (Aβ) deposition, morphological changes of microglia, as well as great impairments of hippocampus neurons but not cortex neurons were observed. The analyze of whole-genome expression in the hippocampus suggested long term PM2.5 exposure changed the expression of genes related with AD process (mouse behavior and microglia differentiation). Furthermore, the mRNA level, which related to microglia, of CD86, CD22, IL-1β was upregulated and CD206, TREM2, TGF-β2 was downregulated. Conclusions: Aged population were more susceptible to long-term PM2.5 exposure and PM2.5 could promote AD-like phenotype through microglia related mechanism.

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