Transcriptome analysis of human dorsal striatum implicates attenuated canonical WNT signaling in neuroinflammation and in age-related impairment of striatal neurogenesis and synaptic plasticity

Article type: Research Article

Authors: Wu, Chun^{a; *} | Bendriem, Raphael M.^b | Freed, William J.^c | Lee, Chun-Ting^{d; *}

Affiliations: [a] Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, USA | [b] Brain and Mind Research Institute, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA | [c] Department of Biology, Lebanon Valley College, Annville, PA, USA | [d] Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA

Correspondence: [*] Corresponding author: Chun Wu, Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, 1951 NW 7th Ave, Suite 240, Miami, FL 33136, USA. Tel.: +1 305 343 6058; E-mail: [email protected]; Chun-Ting Lee, Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Tel.: +1 443 895 8011; E-mail: [email protected].

Abstract: Background:Motor and cognitive decline as part of the normal aging process is linked to alterations in synaptic plasticity and reduction of adult neurogenesis in the dorsal striatum. Neuroinflammation, particularly in the form of microglial activation, is suggested to contribute to these age-associated changes. Objective and Methods:To explore the molecular basis of alterations in striatal function during aging we analyzed RNA-Seq data for 117 postmortem human dorsal caudate samples and 97 putamen samples acquired through GTEx. Results:Increased expression of neuroinflammatory transcripts including TREM2, MHC II molecules HLA-DMB, HLA-DQA2, HLA-DPA1, HLA-DPB1, HLA-DMA and HLA-DRA, complement genes C1QA, C1QB, CIQC and C3AR1, and MHCI molecules HLA-B and HLA-F was identified. We also identified down-regulation of transcripts involved in neurogenesis, synaptogenesis, and synaptic pruning, including DCX, CX3CL1, and CD200, and the canonical WNTs WNT7A, WNT7B, and WNT8A. The canonical WNT signaling pathway has previously been shown to mediate adult neurogenesis and synapse formation and growth. Recent findings also highlight the link between WNT/β-catenin signaling and inflammation pathways. Conclusions:These findings suggest that age-dependent attenuation of canonical WNT signaling plays a pivotal role in regulating striatal plasticity during aging. Dysregulation of WNT/β-catenin signaling via astrocyte–microglial interactions is suggested to be a novel mechanism that drives the decline of striatal neurogenesis and altered synaptic connectivity and plasticity, leading to a subsequent decrease in motor and cognitive performance with age. These findings may aid in the development of therapies targeting WNT/β-catenin signaling to combat cognitive and motor impairments associated with aging.

Keywords: RNA sequencing, caudate, putamen, aging, WNT, striatal neurogenesis, synaptic plasticity, neuroinflammation

DOI: 10.3233/RNN-211161

Journal: Restorative Neurology and Neuroscience, vol. 39, no. 4, pp. 247-266, 2021