Cholinergic basal forebrain (CBF) neurons display the classic hallmark lesion of AD, neurofibrillary tangles (NFT) prior to the cognitive decline seen in AD . Although cholinesterase inhibitors remain the mainstay for the management of mild to moderate AD, these drugs produce only moderate benefits to cognition in AD''. Earlier treatment provides a greater response, highlighting the need to define the pathogenic mechanisms underlying CBF neurodegeneration early in the disease. The CBF connectome consists of four cytoarchitectonic subfieids, anterior medial (Ch4am), anterolateral (Ch4al), intermediate dorsal (Ch4id)/ventral (Ch4iv) and posterior (Ch4p) subfieids, which innervate select cortical regions in a semi topographical pattern. The magnitude of cholinergic neuronal loss within the Ch4 subfieids of AD patients displays subregional variations with the greatest loss in Ch4p, which projects to medial temporal cortex followed by Ch4i which projects to the parietal lobule. Ch4am is the least affected subfield;it innervates medial parietal cortex."""""""" All three areas are involved in cognitive processing. This suggests a spatiotemporal course of Ch4 cellular dysfunction similar to the selective disconnection of the medial temporal entorhinalhippocampal circuit in AD. During the current grant period we found that an antibody that recognized tau phosphorylated at S422 (pS422) is a very early marker of tau's disease-association, localizing within pretangle Ch4 neurons in prodromal AD. Moreover, localization of this phospho-epitope correlated better with cognitive decline than did frank NFTs that contain tau truncated at D421 cleaved by caspase . This critical observation suggests the, existence of separate toxic pools of tau independent of NFT formation. Herein, we provide novel preliminary evidence for the existence of oligomeric tau species that form from dimers. Recently, the role of protein oligomeric aggregation intermediate has received considerable attention in AD because of their link to toxicity"""""""". Importantly;our collaborative PPG group has contributed to the concept of a linear tau epitope model for NFT evolution, which can be tracked by well-characterized antibodies to site-specific tau epitopes marking pretangle, intermediate;and late stages of NFT formation . These antibodies combined with our novel tau oligomer and PAD antibodies will be used to determine the trajectory of the earliest evolution of NFT tau alterations within discrete Ch4 subfieids (see Preliminary data) in preclinical phases of the disease compared to subjects with a diagnosis of MCI. It is now well established that certain forms of tau can have toxic effects on neurons, which underlie the onset of various tauopathies including AD. The development of pathological-tau-containing neurons within the CBF subfieids is a major event in prodromal AD. Since tau has been shown to be the main protein in NFTs, it seemed logical that the mere aggregation of tau into filaments and NFTs was responsible for at least some part of the cellular degenerative cascade underlying cognitive decline. More recently, models of beta-amyloid (A(3) toxicity in culture and in transgenic mice''were shown to depend on the presence of tau;if the tau gene was absent, AB was not toxic to cultured neurons and amyloid precursor protein (APP) transgenic mice did not display behavioral deficits. It is interesting to note, however, that in neither of these cases did tau form NFTs or any obvious aggregates. Additionally, NFTs are believed to persist in neurons for 20-30 years making them unlikely candidates for catalyzing immediate toxicity, yet stereological studies support significant neuronal loss in both MCI and AD . In this regard, our study on CBF neurons in the NBM demonstrated that pretangle neuron and neuropil thread staining with the early tau marker, pS422, correlated extremely well With cognitive decline long before the emergence of significant frank NFT pathology . Moreover, synaptic loss correlates better with cognitive decline than NFTs, again suggesting the possibility of a """"""""pretangle"""""""" tau toxicity. Until recently, the nature of this """"""""pre-tangle tau"""""""" moiety remained elusive. Perhaps the most widely held view was that aggregates physically occluded neuronal processes leading to neuronal dysfunction and death. The most elegant support for this contention comes from work of the Mandelkow lab in which they overexpress a truncated, proaggregate construct of tau that results in neuronal death in transgenic mice. However, in AD, tau aggregates as a full-length molecule and it is not overexpressed in the disease. Another possibility is that tau aggregates sequester tau from the microtubule, causing it to become unstable. Support for this contention comes from transgenic mouse work in which tauopathy mice are treated with, a microtubule stabilizing compound. More recently, our work has suggested that tau aggregates and even certain conformations of tau monomers can lead to unmasking of the PAD region of tau (amino acids 2-18), resulting in inhibition of PP1, activation of GSK3 and inhibition of anterograde transport . Additionally, the PAD region ends in Y18, the fyn site on human tau;phosphorylation of tau with fyn prevents tau aggregates from inhibiting anterograde FAT. Moreover, others have presented evidence indicating that defects in axonal transport were likely causing neuronal dysfunction in AD and other tauopathies. Therefore, we seek to determine what tau alterations affect unmasking of the PAD region as assessed by binding of our PAD-specific antibody, TNT1 and what genes are expressed that can be associated with potential tau toxicity within the Ch4 subfieids (Aims 1 and 2). Data from our laboratory indicates that, during aggregation, tau first dimerizes prior to forming oligomers that presumably can transition to filaments . During this process, the PAD region, generally unavailable in monomers, becomes unmasked as oligomers form (see Section 3, below). Although we previously assumed the polymeric filaments were the toxic species of tau, recently, Hsp70, a tau binding protein, was shown to prevent the tau aggregate inhibition of anterograde transport in the squid model by binding to oligomers and not filaments. It now appears that most of the toxic potential in full-length tau is displayed in the oligomer and our monoclonal antibodies selective for the oligomer (T0C1) and specific for the PAD region on tau (TNT1) allow us to ascertain in situ, 1;when tau is likely in an oligomeric state;and, 2. When the toxic PAD domain is displayed (Aim 1). From this we can infer when axonal transport is becoming dysfunctional in the transition from prodromal to authentic AD by following the evolution and spread of the tau staining patterns in the Ch4 subfieids during the progression of AD. Furthermore, using our in vitro aggregation assays and recombinant technology, we can also approach the mechanisms of PAD unmasking and oligomer formation (Aim 3) while determining which oligomers are most toxic (Aim 4).

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