Editors' ChoiceAlzheimer’s Disease

Preventing an unholy alliance

See allHide authors and affiliations

Science Translational Medicine  25 Mar 2015:
Vol. 7, Issue 280, pp. 280ec51
DOI: 10.1126/scitranslmed.aaa9875

For years, arguments have raged over the relative importance of amyloid-beta (Aβ) and tau in the pathogenesis of Alzheimer’s disease (AD). Aggregates of both proteins, Aβ in the form of amyloid plaques and tau as neurofibrillary tangles, are the pathological hallmarks of AD. Although Aβ plaques appear first, tau pathology is more closely with neurodegeneration. Recent evidence has revealed common ground between the Aβ and tau camps, suggesting that aggregated forms of Aβ may actually trigger tau pathology, leading to downstream neurodegeneration One proposed mechanism for this phenomenon is via Aβ-mediated activation of the Src-family kinase Fyn, which in turn phosphorylates tau and instigates tau-mediated neurodegeneration. Several groups have used genetic approaches to demonstrate that Fyn is required for Aβ-induced tau phosphorylation and neuronal injury, and preventing Aβ-mediated activation of Fyn has thus become an attractive therapeutic strategy for AD.

In a new study, Strittmatter and colleagues describe a potential pharmacological strategy for blocking the destructive Aβ-Fyn-tau axis. The investigators repurposed, as a Fyn inhibitor, an existing Src-family kinase inhibitor, AZD0530, which was originally developed as an anticancer agent. AZD0530 readily crossed the blood-brain barrier and potently inhibited Fyn, leading to decreased phosphorylation of the Fyn target Pyk2. In a mouse model of β-amyloidosis, AZD0530 did not impact Aβ plaque deposition but did mitigate Aβ-induced neuroinflammation and synapse loss, leading to improvements on behavioral tests. In a second AD mouse model that develops both, Aβ plaques and tau pathology, AZD0530 treatment suppressed pathological tau phosphorylation and formation of insoluble tau aggregates. The drug exhibited no overt toxicity after nearly a year of chronic dosing in dogs and also appeared to be safe and well tolerated in previous clinical trials with cancer patients.

The recent failure of several large AD clinical trials with drugs that target Aβ has prompted concerns that Aβ pathology might occur so early in the disease that it is not therapeutically tractable. Preventing Aβ from triggering downstream tau pathology holds great therapeutic potential, as existing biomarkers can identify at-risk presymptomatic individuals who harbor amyloid plaques but do not yet exhibit significant tau aggregation. Treating people in this critical window with a drug such as AZD0530 might have the potential to stall the progression of AD prior to symptom onset. Whereas the off-target effects of broad Src kinase inhibition in the aged brain are unknown and potentially concerning, and studies in humans are lacking, the new work represent a tangible step forward toward a possible AD disease-modifying therapy.

A. C. Kaufman et al., Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann. Neurol. 10.1002/ana.24394 (2015). [Full Text]

Navigate This Article