The contribution of src family kinases to synaptic function and plasticity in adult wild-type mice and an inducible mouse model of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, yet there are no drugs available that can prevent or slow disease progression. One reason for this could be because research focussed on treating individuals with mid-to-late AD who present with extensive and potentially irreversible damage. Increasing research is now investigating therapies to target much earlier pathological events in earlier stages of AD. By the point of AD diagnosis, >50% of CA1 hippocampal synapses have already been lost. Furthermore, synaptic plasticity deficits occur before and could be causative of synapse loss. Therefore, understanding the mechanisms driving synaptic plasticity deficits in AD is an attractive area of research that could aid the discovery of new treatments for early AD intervention.
One potential candidate contributing to plasticity and synapse loss is Fyn kinase (Fyn), a member of the Src family kinases (SFKs). Post-mortem AD tissue and AD mouse models show increased Fyn activity or phosphorylation of Fyn targets. Fyn phosphorylates Y1472 of GluN2B subunits of the NMDAR, stabilising NMDARs at the synapse. Enhanced Fyn activity in AD is proposed to over-stabilise GluN2B-containing NMDARs and increase NMDAR signalling, which could promote excitotoxicity and contribute to the loss of plasticity and synapses.
Using an inducible mouse model of AD (Line 102) to induce APPSwe/Ind expression in adult mice, we analysed mice when synaptic plasticity deficits first arise in CA3-CA1 synapses (after 3 weeks of APPSwe/Ind expression). We show enhanced GluN2B pY1472, consistent with increased Fyn activity. To test whether increased Fyn activity contributes to reduced synaptic plasticity, we measured long-term potentiation (LTP) in hippocampal slices from these mice following inhibition of Fyn with Saracatinib, a drug approved for human use with repurposing potentials for AD.
Acute Saracatinib treatment reduced Y1472-GluN2B phosphorylation, and whilst it did not alter LTP in adult WT mice, it rescued the LTP impairment in Line 102 mice. This suggests that increased Fyn activity may contribute to plasticity impairments in this model. However, since Saracatinib is a broad SFK inhibitor, further research is required using more Fyn-specific drugs to determine whether Fyn inhibition is responsible for rescuing plasticity. Acute Saracatinib treatment did not rescue impaired synaptic transmission that occurred later in Line 102 mice, suggesting a narrow therapeutic window of Saracatinib. This thesis supports the evidence suggesting increased Fyn activity in AD, and our results suggest that this increase may occur early in disease progression, possibly before symptom onset. The findings in this project contribute to our understanding of the mechanisms that underlie early AD pathology and add further support to the future use of SFK inhibitors to treat AD.

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Identifiers

ORCID for Lauren McNicholas: orcid.org/0009-0009-9949-7910

ORCID for Mariana Vargas-Caballero: orcid.org/0000-0003-2326-4001

ORCID for Katrin Deinhardt: orcid.org/0000-0002-6473-5298

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