Abstract
BackgroundThe 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.MethodsIn 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.ResultsWe 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.ConclusionIn 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.
Highlights
The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treat‐ ments
We measured the slope of the field excitatory postsynaptic potential recorded from the stratum radiatum of CA1, as a function of the stimulation intensity applied to the Schaffer collateral fibres
We report that basal transmission and longterm potentiation (LTP) are rescued in Mice co-expressing five familial Alzheimer’s disease mutations (5xFAD)/ fatty acid amide hydrolase (FAAH)−/− animals, and that this effect is independent of CB1 receptor (CB1R) or Transient receptor potential vanilloid 1 (TRPV1) receptor activation
Summary
The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treat‐ ments. Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that threatens to impose an unbearable social and economic burden in the years to come due to the lack of effective treatments [1]. It entails a complex pathophysiological scenario, with progressive incapacitating dementia as its main hallmark. Neuroinflammation is usually defined as a “doubleedged sword”, as its specific consequences, either beneficial or detrimental, seem to intimately depend on the context in which it is taking place It appears to be crucially influenced by neuron–glia interaction. A third layer of complexity is added by the bidirectional communication between astrocytes and microglia, that shapes their reactivity and ability to respond to a varied range of stimuli in the CNS [6]
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