Vaccination with Abeta

A set of experiments just completed in our lab provides strong evidence to support the amyloid hypothesis of AD. As described above, this hypothesis states that Aβ production and deposition lead in sequential fashion to tau hyperphosphorylation and aggregation forming neurofibrillary tangles, which leads, in turn, to neuronal loss and cognitive decline. If true, then reducing levels of amyloid to stop downstream pathologies is a logical test of the hypothesis. To date, animal studies on vaccination to reduce brain amyloid have only examined restricted changes in AD pathology such as amyloid deposition or tau pathology composed of mutant human tau that is not truly representative of AD (see our recent review article below on vaccination as a therapy for AD). While providing useful information, these limited models do not prove the amyloid hypothesis or demonstrate if targeting amyloid is sufficient to reduce pathological tau and neuronal loss.

Using our novel AD models, Abeta1-42, or KLH vaccinations were started at 12 months of age (when disease progression and cognitive deficits are underway) and continued for 4 months. Vaccinated APPSwDI/NOS2-/- mice, which have predominantly vascular amyloid pathology, showed decreased brain Abeta (30%) and reduced tau hyperphosphorylation (30-40%). Neuron loss and cognitive deficits were partially reduced compared to mice receiving control vaccination. In APPSw/NOS2-/- vaccinated mice, brain Aβ was reduced by 65-85% and hyperphosphorylated tau by 50-60%. Lowering amyloid prevented any further neuron loss and completely reversed memory deficits in these mice. Importantly, microhemorrhage was observed in all vaccinated APPSw/NOS2-/- mice. While the study bolsters the confidence in amyloid as a therapeutic target for AD, the presence of numerous small sites of bleeding into the brain raises a red flag for the use of vaccination as a treatment for AD. Non-amyloid directed therapeutic approaches are thus much needed, and may provide adjunct or bypass therapies. These experiments are ongoing.

Testing therapeutics in our mouse model of AD. We are eager to explore partnerships with academic collaborators and with companies to test therapeutic compounds or approaches in our bigenic mouse models of AD. Most recently, we are working with Cognosci, Inc. RTP NC to test their novel peptides on AD-like pathogenesis.

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