Therapeutic potential of secreted APPsalpha for Tau associated synaptic dysfunction and pathology

• Applicant: Professorin Dr. Ulrike Müller
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 342000669

Alzheimer's disease (AD) is characterized by synaptic dysfunction, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. Two major pathological lesions are hallmark features of AD: neurofibrillary tangles (NFT), composed of aggregated hyperphosphorylated Tau protein and extracellular plaques consisting of Abeta peptides derived from the amyloid precursor protein APP by proteolytical processing. Despite a recent shift towards preventive strategies there is still an urgent need for an effective treatment of patients with clinically established AD. Accumulating evidence indicates that not only the build up of NFTs and Abeta leads to AD, but that loss of physiological APP functions mediated predominantly by the neurotrophic, secreted APPsalpha produced in the alternative non-amyloidogenic pathway contributes to AD pathogenesis. Our previous work indicated a crucial role of APPsalpha for neuroprotection against various forms of cellular stress in vitro and an essential in vivo role of endogenous APPsalpha for synaptic plasticity and cognition. To explore the therapeutic potential of APPsalpha we recently used an AAV based gene therapy approach (to overexpress APPsalpha in the brain of transgenic AD model mice with plaque pathology. Strikingly, we could show that AVV-mediated overexpression of APPsalpha in aged transgenic APP/PS1deltaE9 mice with well established plaque pathology restored synaptic plasticity and rescued spine density deficits. Importantly, AAV-APPsalpha treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Here, our goal is to test the more general applicability of APPsalpha treatment for neurodegenerative diseases. In particular, it is unknown whether APPsalpha is also beneficial in mice with Tau pathology, the prominent second hallmark of AD and several other tauopathies. To this end we intend to assess AAV-APPsalpha mediated beneficial effects in a transgenic mouse lines expressing disease associated mutant Tau isoforms. APPsalpha will be expressed either before the onset of Tau pathology (preventive approach) or at later stages with already established pathology (curative approach). This way, we will assess the potential of APPsalpha to ameliorate or rescue Tau induced pathology including effects on synaptic density, synaptic plasticity, neuronal loss and cognitive behavior. Moreover, we intend to delineate the minimal APPsalpha functional domain, which is very important for future therapeutic application. Finally, we intend to get further insight into the molecular mechanisms underlying APPsalpha mediated effects and identify its molecular targets.

• DFG Programme: Research Grants