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Young blood plasma reduces Alzheimer's disease-like brain pathologies and ameliorates cognitive impairment in 3×Tg-AD mice.

ABSTRACT: BACKGROUND:Recent studies indicated that circulatory factors in blood plasma from young animals can reactivate neurogenesis, restore synaptic plasticity, and improve cognitive function in aged animals. Here, we investigated if young plasma could have a possible therapeutic effect for treatment of Alzheimer's disease (AD)-like pathologies and cognitive impairment in triple-transgenic AD (3×Tg-AD) mice. METHODS:We intravenously injected plasma from 2- to 3-month-old C57BL/6?J wild-type mice into 16-17-month-old 3×Tg-AD mice twice a week for 8?weeks. The behavioral tests including open field, novel object recognition, Morris water maze, and reversal Morris water maze were conducted after 4-week plasma injections. The effect of young plasma on tau and A? pathologies and on the levels of synaptic proteins and neuroinflammation were assessed by Western blots and immunohistochemical staining. RESULTS:Young plasma treatment improved short-term memory in the novel object recognition test and enhanced the spatial learning and memory in Morris water maze test and reversal Morris water maze test. Biochemical studies revealed that young plasma treatment reduced both tau and A? pathologies, as well as neuroinflammation in the mouse brain. However, we did not detect any significant changes in levels of synaptic proteins or the dentate gyrus neurogenesis in the mouse brain after the treatment with young plasma. CONCLUSIONS:These data indicate that young blood plasma not only ameliorates tau and A? pathologies but also enhances the cognitive function in 3×Tg-AD mice. These findings suggest that transfusion with young blood plasma could be a potentially effective treatment for AD.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC7278124 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Young blood plasma reduces Alzheimer's disease-like brain pathologies and ameliorates cognitive impairment in 3×Tg-AD mice.

Zhao Ying Y Qian Ran R Zhang Jin J Liu Fei F Iqbal Khalid K Dai Chun-Ling CL Gong Cheng-Xin CX

Alzheimer's research & therapy 20200608 1

<h4>Background</h4>Recent studies indicated that circulatory factors in blood plasma from young animals can reactivate neurogenesis, restore synaptic plasticity, and improve cognitive function in aged animals. Here, we investigated if young plasma could have a possible therapeutic effect for treatment of Alzheimer's disease (AD)-like pathologies and cognitive impairment in triple-transgenic AD (3×Tg-AD) mice.<h4>Methods</h4>We intravenously injected plasma from 2- to 3-month-old C57BL/6 J wild-t ...[more]

PMID: 32513253

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Project description:RationaleHyperglycemia accelerates the progression of Alzheimer's disease (AD), and GSK3? plays a potential link between AD and hyperglycemia. Therefore, a direct or indirect GSK3? inhibition may have potential to delay the progression of AD. Our previous biochemical assay identified AM404 as a GSK3? inhibitor at high dose (IC50?=?5.353 ?M); however, other study suggests that AM404 impaired synaptic plasticity of hippocampus at high dose (10 mg/kg; i.p.). Therefore, the dose and duration of treatment are crucial for the effects of AM404.ObjectiveThe effects and molecular mechanisms of AM404 at low dose were evaluated from in vitro to in vivo models.MethodsAM404 (0.1-0.5 ?M) was tested on tau hyperphosphorylated mouse hippocampal primary cultures treated with Wortmannin (WT) and GF109203X (GFX). Hyperglycemic triple transgenic AD (3×Tg-AD) mice at 6 months old were intraperitoneally injected with AM404 (0.25 mg/kg) for 4 weeks. The spatial learning and memory of mice were measured using the Morris water maze. Mouse brain and serum samples were collected for pathological analyses.ResultsAM404 (0.5 ?M) exhibited significantly augmented neuroprotection toward tau hyperphosphorylation in primary cultures. The chronic systemic administration of AM404 (0.25 mg/kg) attenuated cognitive deficits in hyperglycemic 3×Tg-AD mice. Moreover, chronic low dose of AM404 significantly attenuated A? production, tau protein phosphorylation, and inflammation associated with an increase of pS473Akt and pS9-GSK3?. Therefore, AM404 at low dose, not only increased neuroprotection, but also ameliorated cognitive deficit, could be partly by regulating the Akt/GSK3? signaling, which may contribute to downregulation of A?, tau hyperphosphorylation, and inflammation in hyperglycemic 3×Tg-AD mice.ConclusionsThese results highlight that chronic administration of AM404 at low dose may be through the Akt/GSK3? pathway to ameliorate the impairment in hyperglycemic 3×Tg-AD mice.

Dataset Information

Young blood plasma reduces Alzheimer's disease-like brain pathologies and ameliorates cognitive impairment in 3×Tg-AD mice.

Publications

Young blood plasma reduces Alzheimer's disease-like brain pathologies and ameliorates cognitive impairment in 3×Tg-AD mice.

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