Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer’s disease.
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2021
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Journal of Neuroinflammation
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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 longterm
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