Amyloid and Tau Neuropathology Differentially Affect Prefrontal Synaptic Plasticity and Cognitive Performance in Mouse Models of Alzheimer's Disease

Reduced glucose utilization and deficient energy metabolism that occur in the early stages of Alzheimer’s disease correlate with impaired cognition, and this information is evidence that Alzheimer’s disease is a metabolic disease that is associated with brain insulin/insulin-like growth factor resistance. This research aimed to investigate the effects of Banxia Xiexin decoction (BXD) on cognitive deficits in APPswe/PS1dE9 double transgenic mice and verify the hypothesis that BXD treatment improves cognitive function via improving insulin signalling, glucose metabolism and synaptic plasticity in the hippocampus of APPswe/PS1dE9 double transgenic mice. We used 3-month-old APPswe/PS1dE9 double transgenic mice as the case groups and wild-type littermates of the double transgenic mice from the same colony as the control group. Forty-five APPswe/PS1dE9 double transgenic mice were randomly divided into the model group, donepezil group and BXD group. The mice in the control and model groups were administered 0.5% carboxymethyl cellulose orally. The Morris water maze and step-down test were conducted to evaluate the cognitive performance of APPswe/PS1dE9 double transgenic mice after BXD treatment. Ultrastructure of synapses was observed in the hippocampal CA1 area. Proteins involved in insulin signalling pathways and glucose transports in the hippocampus were assessed through immunohistochemical staining and western blot. After 3 months intervention, we found that BXD treatment improved cognitive performance and the synaptic quantity and ultrastructure, restored insulin signalling and increased the expression of glucose transporter 1 (GLUT1) and GLUT3 levels. These findings suggest that the beneficial effect of BXD on cognition may be due to the improvement of insulin signalling, glucose metabolism and synaptic plasticity.

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P2-162: EXERCISE-LINKED FNDC5/IRISIN CORRECTS SYNAPTIC PLASTICITY AND MEMORY DEFECTS IN MOUSE MODELS OF ALZHEIMER'S DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.2569 ◽

2019 ◽

Vol 15 ◽

pp. P637-P638

Author(s):

Mychael V. Lourenco ◽

Ottavio Arancio ◽

Sergio Teixeira Ferreira ◽

Fernanda Guarino De Felice

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Mouse Models

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O5-03-05: Brain Sirtuin-2 Inhibition Improves Cognitive Performance and Affects Beta-Amyloid Processing in two Alzheimer’s Disease Mouse Models

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.720 ◽

2016 ◽

Vol 12 ◽

pp. P384-P384

Author(s):

Gianluigi Forloni ◽

Federica Fusco ◽

Gloria Biella ◽

Annarosaria Agrillo ◽

Diego Albani

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Performance ◽

Mouse Models ◽

Beta Amyloid

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Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity and memory in mouse models of Alzheimer’s disease

10.1101/2020.10.19.344564 ◽

2020 ◽

Author(s):

Mauricio M. Oliveira ◽

Mychael V. Lourenco ◽

Francesco Longo ◽

Nicole P. Kasica ◽

Wenzhong Yang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Synthesis ◽

Synaptic Plasticity ◽

Mouse Models ◽

Translation Initiation ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Long Term Memory

AbstractNeuronal protein synthesis is essential for long-term memory consolidation. Conversely, dysregulation of protein synthesis has been implicated in a number of neurodegenerative disorders, including Alzheimer’s disease (AD). Several types of cellular stress trigger the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α-P). This leads to attenuation of cap-dependent mRNA translation, a component of the integrated stress response (ISR). We show that AD brains exhibit increased eIF2α-P and reduced eIF2B, key components of the eIF2 translation initiation complex. We further demonstrate that attenuating the ISR with the small molecule compound ISRIB (ISR Inhibitor) rescues hippocampal protein synthesis and corrects impaired synaptic plasticity and memory in mouse models of AD. Our findings suggest that attenuating eIF2α-P-mediated translational inhibition may comprise an effective approach to alleviate cognitive decline in AD.

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Restoring synaptic plasticity and memory in mouse models of Alzheimer’s disease by PKR inhibition

Molecular Brain ◽

10.1186/s13041-017-0338-3 ◽

2017 ◽

Vol 10 (1) ◽

Cited By ~ 16

Author(s):

Kyoung-Doo Hwang ◽

Myeong Seong Bak ◽

Sang Jeong Kim ◽

Sangmyung Rhee ◽

Yong-Seok Lee

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Mouse Models

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Faculty Opinions recommendation of Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718892324.793502581 ◽

2014 ◽

Author(s):

Y Peng Loh ◽

Jane Huang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Amyloid Β

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Evaluating Thrombin Inhibition in Alzheimer’s Disease (The BEACON Trial): Protocol for a Pilot Study (Preprint)

10.2196/preprints.14905 ◽

2019 ◽

Author(s):

Cláudia Yang Santos ◽

Christine Getter ◽

John Stoukides ◽

Brian Ott ◽

Stephen Salloway ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pilot Study ◽

Cognitive Performance ◽

Thrombin Inhibitor ◽

Placebo Control ◽

Open Label ◽

Double Blind ◽

Thrombin Inhibition ◽

Approved Drugs

BACKGROUND The precise mechanisms whereby cardiovascular risk factors increase the risk of Alzheimer’s disease (AD) have not been delineated. We reported that microvessels isolated from AD brains overexpress a diverse array of neurotoxic and inflammatory proteins, which is consistent with the process of vascular activation. In pre-clinical studies using AD animal models we showed that a vascular activation inhibitor reduced vascular-derived neuroinflammation and improved cognitive performance. Thrombin is a key mediator of cerebrovascular activation in AD. OBJECTIVE This study aims to investigate the safety and potential efficacy of the direct thrombin inhibitor dabigatran, in patients with mild cognitive impairment (MCI) or mild AD to decrease vascular-derived neuroinflammation and improve cognitive performance. METHODS Participants will be enrolled then evaluated quarterly throughout the 24-month study. This is a 24-month randomized-control, double-blind, placebo-controlled, multicenter, delayed-start, pilot study evaluating thrombin inhibition in people with biomarker-confirmed MCI probably due to AD or mild AD. 40 - 60 participants will be recruited between 50 - 85 years old. In the initial 9-months of study, either dabigatran or placebo will be orally administered to patients at a dose of 150 mg per day. After 9 months of the placebo-control (Phase I), the placebo arm will cross-over to an active, open-label (Phase II) where all patients will be treated with a 150 mg daily dose of dabigatran orally for an additional 12 months. A 3-month non-treatment follow-up period will assess duration of effects. RESULTS Beginning in July 2019, and concluding in August 2022, this study is expected to publish final results in January 2023. CONCLUSIONS BEACON is a first-in-kind randomized clinical trial targeting thrombin activation in AD therapeutics. This trial will stimulate translational investigations of an FDA-approved drugs in a newly defined therapeutic areas. CLINICALTRIAL Clinicaltrials.gov NCT03752294

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