A Study to Validate Tau as a Therapeutic Target for Alzheimer's Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized clinically by a progressive cognitive decline and severe memory loss. Pathologically, Alzheimer’s is diagnosed by the presence of amyloid plaques composed of aggregated amyloid-beta (Aâ) peptides, neurofibrillary tangles composed of hyperphosphorylated and aggregated tau, and neuron loss. The main question for the development of effective treatments for Alzheimer’s disease is, which of these pathologies is the best target of therapeutic interventions? To date, Aâ and amyloid deposition have been extensively targeted. This is a logical approach based on the centrality of amyloid to the amyloid hypothesis of AD, which states that excess Aâ deposition in the brain leads in a sequential fashion to tau hyperphosphorylation, formation of tau aggregates leading to neuronal loss and cognitive decline. A major obstacle in the study of AD and in the development of successful therapeutics has been a lack of animal models that demonstrate complete AD-like pathology. Many models have used mutations in the amyloid precursor protein (APP, cleaved to produce Aâ) that are known to cause early-onset familial AD to increase amyloid deposition. However, these mice typically lacked extensive tau pathology or neuron loss and thus have not provided direct confirmation of the amyloid hypothesis. In order to generate tau pathology in mice, transgenic mice were developed carrying mutated human tau known to cause fronto-temporal dementia, but not AD. We have developed transgenic mouse models that more closely mimic Alzheimer’s disease, that show not only amyloid deposits but also tau pathology and neuron loss. These mice were generated by genetic deletion of the nitric oxide synthase 2 gene, NOS2, in APP transgenic mice, which we believe reduces nitric oxide levels in the mouse brain, removing a potential protective mechanism and now allowing progression of pathology. The first mouse, the APPSw/NOS2-/-, develops significant parenchymal amyloid deposits with some vascular involvement, tau hyperphosphorylation and aggregation and 30% hippocampal neuron loss by 12 months of age. The second mouse, the APPSwDI/NOS2-/-, develops significant vascular amyloid deposits with some parenchymal amyloid, tau hyperphosphorylation and aggregation and 35% hippocampal neuron loss at 12 months. Both show significant cognitive deficits at 12 months of age. It is important to note that NOS2-/- mice alone do not develop any abnormal brain pathology. We now show that removal of amyloid deposition in both APP/NOS2-/- mouse models by Aâ vaccination results not only in lower amyloid load, but also lowers tau hyperphosphorylation, reverses memory deficits and preserves viable neurons (manuscript in preparation). However, brain microhemorrhage is also increased in vaccinated mice. The increased incidence of microhemorrhage is an adverse event that may reduce the long-term effectiveness of amyloid-based treatment. Recently, therapeutic compounds have been developed that inhibit tau hyperphosphorylation. Therefore, approaches targeting tau may avoid this adverse event . Critical unanswered questions on a tau-based approach remain. For example, what effect will targeting tau hyperphosphorylation alone have on the other pathologies of Alzheimer’s disease and, ultimately, learning and memory? We are uniquely positioned to address this critical question using our mouse models. We will use two treatments to affect tau pathology. The first is lithium, which has been shown to significantly reduce tau hyperphosphorylation by inhibition of glycogen synthase kinase 3 (GSK3). The second drug is COG112, developed by Cognosci Incorporated. This drug has been shown to increase protein phosphatase 2a (PP2A) activity through the inhibition of SET. PP2A is the main serine-threonine phosphatase that dephosphorylates pathological tau. We plan to perform two studies: a reversal study, beginning treatment when significant pathology is already present, and a prevention study, beginning prior to onset of pathology. In all cases, we will measure amyloid deposition, tau pathology, neuronal loss and behavior as outcomes. It is possible that these therapies will also affect APP so we will treat APP only mice to assess independent effects on amyloid deposition. Overall, the data obtained in these studies will present a clearer picture as to where in the pathological cascade of Alzheimer’s disease therapies should be targeted.