The cognitive decline in Alzheimer's disease (AD) correlates with tau pathology or CSF tau. However, the pathogenic tau species and the mechanisms underlying tau toxicity in AD remain elusive. Our recent study points to important pathogenic roles for aberrantly acetylated tau (ac-tau) species, whose levels are elevated in NFTs, and the elevation is associated with cognitive impairment in AD. A critical trigger of tau-mediated toxicity in AD is elevated somatodendritic tau. We showed that tau acetylation on K274 and K281 destabilizes the barrier in the axon initial segment (AIS) and elevates levels of somatodendritic tau. Mice expressing mutant tau that mimics acetylation (KQ) exhibited impaired synaptic plasticity and spatial memory. Our study further linked tau-mediated synaptic plasticity impairment with deficiency in KIBRA, post-synaptic scaffolding protein. While KIBRA is reduced in AD brains, elevating KIBRA expression prevented KQ-induced LTP deficits in rat neurons. We propose to further dissect the mechanisms underlying ac-tau-mediated deficits in synaptic plasticity and memory by combining human neuron and mouse models.
In Aim 1, we will focus on the effects of ac-tau on the AIS, which plays a critical role in restricting axonal protein from somatodendritic compartments in human neurons. We will use our newly established inducible pluripotent stem cells (iPSCs)-derived human neuron platform and CRISPR/cas9 genomic editing to establish isogenic lines that express acetyl-mimicking tau at endogenous levels. We will then collaborate with Dr. Ke Xu and use stochastic optical reconstruction microscopy (STORM) to image AIS structural proteins and tau distribution in axons and dendrites of human neurons at single-molecule resolution.
In Aim 2, we will directly determine whether ac-tau gains access to dendritic spines by destabilizing the AIS using a combination of STORM and live imaging. In human iPSC neurons, we will assess the effects of ac-tau on microtubule dynamics and stability, particularly at AIS, using fluorescence recovery after photobleaching. We will then compare the extent to which WT and KQ tau cross the AIS and determine whether restoring AIS barrier function specifically using caged taxol would normalize tau distribution.
In Aim 3, we will dissect the post-synaptic mechanisms underlying tau-mediated synaptic plasticity and cognition. To determine if deficiency in KIBRA is a driver in tau-mediated synaptic deficits, we test if lowering KIBRA levels is sufficient to cause tau-mediated synaptic deficits by deleting one allele of KIBRA in mice expressing human wildtype tau. Various domains of KIBRA interact directly with postsynaptic proteins, including PICK1, synaptopodin, dendrin, dynein, and PKM?, to regulate actin cytoskeleton and/or AMPAR trafficking. Using KIBRA mutants containing specific signaling domains, we propose to identify which KIBRA-mediated signaling plays a critical role in tau-mediated synaptic toxicity. By combining mechanistic dissection in human iPSC-derived neurons and in vivo circuit studies in mouse models, we expect to gain novel insights that can be translated into therapies to counteract tau-mediated cognitive decline.
This projects aims to determine the mechanisms that regulate pathogenic tau-induced cognitive deficits and to develop new strategies to enhance cognitive function in Alzheimer's disease. This study may provide new therapeutic avenues for treating this devastating disease.
|Min, Sang-Won; Sohn, Peter Dongmin; Li, Yaqiao et al. (2018) SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy. J Neurosci 38:3680-3688|
|Sayed, Faten A; Telpoukhovskaia, Maria; Kodama, Lay et al. (2018) Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc Natl Acad Sci U S A 115:10172-10177|
|Snyder, Heather M; Carare, Roxana O; DeKosky, Steven T et al. (2018) Military-related risk factors for dementia. Alzheimers Dement 14:1651-1662|
|Martinez-Losa, Magdalena; Tracy, Tara E; Ma, Keran et al. (2018) Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease. Neuron 98:75-89.e5|
|Tracy, Tara E; Gan, Li (2018) Tau-mediated synaptic and neuronal dysfunction in neurodegenerative disease. Curr Opin Neurobiol 51:134-138|
|Boselli, Monica; Lee, Byung-Hoon; Robert, Jessica et al. (2017) An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons. J Biol Chem 292:19209-19225|