Fyn, another kinase implicated in post-translational modification of tau, belongs to the Src family of tyrosine kinases, and in AD overactivation of Fyn has been hypothesized to cause pathologic tau phosphorylation (Tyr18) and synaptic loss via a mechanism dependent on oligomeric Aβ (oAβ) and cellular prion protein (PrPC). [59] A small molecule Fyn inhibitor called saracatinib (AZD0530) was initially developed by AstraZeneca for treatment of various cancers [60]. In transgenic mouse models overexpressing amyloid (APPswe/PS1ΔE9), saracatinib also prevented synaptic loss and rescued memory deficits, and, in the 3xTg triple transgenic mouse, it reduced tau aggregation. [61] A Phase 1 trial in 24 patients with AD showed saracatinib was well-tolerated and showed CNS penetration via oral dosing [62], and these findings led to CONNECT (NCT02167256), a 12-month Phase 2 trial in 159 patients with mild AD, with a primary outcome of 18F-FDGPET. No effect was seen on primary or secondary outcomes, and GI side effects led to discontinuation in a quart of particpants [63].
