Poster abstracts
Poster number 71 submitted by Susan Xu
Molecular mechanisms underlying enhancement of the tripartite glutamatergic synapse by LH001, a clinical candidate compound for Alzheimer’s disease
Zan Xu (OSU neuroscience graduate program), Joshua Foster (OSU department of neuroscience), Xueqin Wang (OSU department of neuroscience), Chien-liang Lin (OSU department of neuroscience)
Abstract:
Tripartite synapse is formed by a pre-synapse, a post-synapse, and a peri-synaptic astrocytic process (PAP) (1). Studies indicate that loss of tripartite glutamatergic synapses is the major correlate of cognitive impairment in Alzheimer’s disease (AD) (1). Restoring tripartite glutamatergic synapse is a potential therapeutic strategy for AD (1). Our laboratory has discovered and developed a novel small molecule named LH001 that can enhance the structure and function of tripartite glutamatergic synapses (2). LH001 can effectively restore tripartite glutamatergic synapses and significantly improve cognitive functions in two mouse models of AD (2,3). However, the molecular mechanisms of LH001 remain to be fully elucidated. In a previous study, we found that LH001 action site is located at the PAP. A set of PAP proteins is rapidly upregulated through local translation following LH001 treatment. Recently, we found that a set of proteins localized to the plasma membrane of the PAP immediately after LH001 treatment. LH001 mediated localization was abolished by inhibition of protein kinase A (PKA), indicating PKA signaling pathway involvement. In addition, subunits of eIF4F complex were found localized to the plasma membrane and were activated by PKA after LH001 treatment. In light of these observations, we hypothesize that LH001 activates PKA signaling pathway resulting in localization and activation of proteins involved in translation at the plasma membrane of the PAP, which increases protein synthesis. To test this hypothesis, we used BONCAT (bio-orthogonal non-canonical amino acid tagging) to label newly synthesized proteins in primary astrocyte cultures. The result showed that LH001 increased protein translation, and this effect was abolished by a PKA inhibitor. We currently i) investigate if LH001 mediated protein translation occurs at the plasma membrane of the PAP ii) identify these newly synthesized proteins, and iii) examine the effects of protein translation at the PAP on the functional and structural plasticity of the tripartite synapses.
References:
1. Rudy CC, Hunsberger HC, Weitzner DS, Reed MN. The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease. Aging Dis. 2015 Mar 10;6(2):131–48.
2. Foster JB, Zhao F, Wang X, Xu Z, Lin K, Askwith CC, et al. Pyridazine-derivatives Enhance Structural and Functional Plasticity of Tripartite Synapse Via Activation of Local Translation in Astrocytic Processes. Neuroscience. 2018 Sep;388:224–38.
3. Takahashi K, Kong Q, Lin Y, Stouffer N, Schulte DA, Lai L, et al. Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer’s disease. J Exp Med. 2015 Mar 9;212(3):319–32.
Keywords: Tripartite synapse, Alzheimers disease, protein translation