Kif11 overexpression rescues cognition, long-term potentiation, and spine defects in mouse and cell models of Alzheimer’s disease

AbstractCompetitive inhibition of kinesin motor proteins by amyloid-beta (Aβ) may contribute to alterations in the neuronal microtubule cytoskeleton that can disrupt plasticity mechanisms required for learning and memory, such as long-term potentiation (LTP), thus contributing to synaptic dysfunction and cognitive impairments associated with Alzheimer’s disease (AD). Here, we tested the hypothesis that overexpression of the microtubule motor protein KIF11 (Kinesin-5/Eg5) will rescue Aβ-mediated synaptic dysfunction and cognitive impairments. We found that overexpression of Kif11 prevented spatial learning and LTP deficits in the 5xFAD mouse model of AD and rescued Aβ-mediated decreases in postsynaptic dendritic spine density in neuronal cultures. Together, these data suggest that KIF11 function is important for preserving synaptic structures and functions that are critical for learning and memory and for protection against Aβ-mediated loss of cognition in AD.HighlightsDeficits in cognition and long-term potentiation in the 5xFAD mouse model of Alzheimer’s disease are prevented by Kif11 overexpression.Aβ-mediated dendritic spine loss is blocked by Kif11 overexpression.

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Decision letter for "Maintained memory and long‐term potentiation in a mouse model of Alzheimer’s disease with both amyloid pathology and human tau"

10.1111/ejn.14918/v2/decision1 ◽

2020 ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Long Term Potentiation ◽

Amyloid Pathology ◽

Model Of Alzheimer’S Disease ◽

Term Potentiation

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Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer's disease

Journal of Neuroinflammation ◽

10.1186/s12974-021-02276-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Gonzalo Ruiz-Pérez ◽

Samuel Ruiz de Martín Esteban ◽

Sharai Marqués ◽

Noelia Aparicio ◽

M. Teresa Grande ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Synaptic Transmission ◽

Amyloid Beta ◽

Molecular Mechanisms ◽

Long Term Potentiation ◽

Genetic Inactivation ◽

5Xfad Mouse

Abstract Background The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treatments. Attempts to prevent neurodegeneration in AD have failed so far, highlighting the need for further clarification of the underlying cellular and molecular mechanisms. Neuroinflammation seems to play a crucial role in disease progression, although its specific contribution to AD pathogenesis remains elusive. We have previously shown that the modulation of the endocannabinoid system (ECS) renders beneficial effects in a context of amyloidosis, which triggers neuroinflammation. In the 5xFAD model, the genetic inactivation of the enzyme that degrades anandamide (AEA), the fatty acid amide hydrolase (FAAH), was associated with a significant amelioration of the memory deficit. Methods In this work, we use electrophysiology, flow cytometry and molecular analysis to evaluate the cellular and molecular mechanisms underlying the improvement associated to the increased endocannabinoid tone in the 5xFAD mouse− model. Results We demonstrate that the chronic enhancement of the endocannabinoid tone rescues hippocampal synaptic plasticity in the 5xFAD mouse model. At the CA3–CA1 synapse, both basal synaptic transmission and long-term potentiation (LTP) of synaptic transmission are normalized upon FAAH genetic inactivation, in a CB1 receptor (CB1R)- and TRPV1 receptor-independent manner. Dendritic spine density in CA1 pyramidal neurons, which is notably decreased in 6-month-old 5xFAD animals, is also restored. Importantly, we reveal that the expression of microglial factors linked to phagocytic activity, such as TREM2 and CTSD, and other factors related to amyloid beta clearance and involved in neuron–glia crosstalk, such as complement component C3 and complement receptor C3AR, are specifically upregulated in 5xFAD/FAAH−/− animals. Conclusion In summary, our findings support the therapeutic potential of modulating, rather than suppressing, neuroinflammation in Alzheimer’s disease. In our model, the long-term enhancement of the endocannabinoid tone triggered augmented microglial activation and amyloid beta phagocytosis, and a consequent reversal in the neuronal phenotype associated to the disease.

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