Linking NPTX2 and Tau pathophysiology in AD

PROJECT SUMMARY Tau pathology in Alzheimer’s disease (AD) is linked to neuronal activity in multiple ways, including an effect of activity to increase tau phosphorylation [1], tau spread between neurons, and tau shedding into the CSF [2], and activity inhibition reduces tau pathology [3]. NPTX2 (Neuronal Pentraxins 2) is an immediate early gene (IEG) that acts specifically at excitatory synapses on parvalbumin interneurons (PV) to regulate circuit inhibition and is prominently down-regulated in the brain of individuals with AD [4]. During its normal function, a portion of synaptic NPTX2 is shed into the cerebrospinal fluid (CSF) where levels in human subjects inversely correlate with cognitive performance and hippocampal volume in MCI and AD [4-6]. One consistent observation in these studies is that a ratio of CSF NPTX2 and tau or ptau prominently increases diagnostic performance [4-6]. This suggests an important relationship between CSF NPTX2 and tau/ptau in AD. NPTX2 is generated by pyramidal neurons (Py) throughout the forebrain and is trafficked along axons to presynaptic sites where it is exocytosed in response to Py activity and functions specifically at excitatory synapses on PV to strengthen the excitatory drive of PVs, thereby enhancing inhibition within the circuit [7, 8]. Consistent with these synaptic effects, NPTX2 loss of function results in increased Py activity and reduced gamma power, and these effects are amplified by Aß amyloidosis [4]. These observations focus attention on potential interactions between NPTX2 loss of function and tau pathophysiology. To examine the interaction of tau with NPTX2, we will use a newly established rat AD model (TgF344-AD) that expresses human FAD mutations including APP (APPswe) and presenilin 1 (PSΔE9) and mimics human disease by developing tau pathology without requiring mutation of tau [9]. Aim 1 will develop novel tools to image tau accumulation in vivo using 2-photon microscopy. Fluorescent tau indicators, termed Tau1 and Tau 2, will be evaluated for detection of tau accumulations in TgF344-AD rats following either i.v. or local injection of the reporters into the brain using a novel perforated cranial window. In vivo 2-photon images of tau will be correlated with histopathologically imaged tau. Aim 2 will examine the impact of conditional deletion of NPTX2 in TgF344-AD rat neocortex on tau accumulation and cellular localization and correlate these parameters with the activity of Py and PV neurons using cutting-edge multi-color longitudinal 2 photon imaging. The proposed research will develop methods to image pathologic tau accumulation in vivo and test the association of pathological forms of tau with NPTX2 loss of function and resulting changes in brain activity.