Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer's Disease

Lily Wan; Jia-Qi Ai; Chen Yang; Juan Jiang; Qi-Lei Zhang; Zhao-Hui Luo; Rou-Jie Huang; Tian Tu; Aihua Pan; Ewen Tu; Jim Manavis; Bo Xiao; Xiao-Xin Yan

doi:10.3389/fnagi.2021.717263

Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer's Disease

Front Aging Neurosci. 2021 Aug 24:13:717263. doi: 10.3389/fnagi.2021.717263. eCollection 2021.

Authors

Lily Wan¹, Jia-Qi Ai², Chen Yang², Juan Jiang², Qi-Lei Zhang², Zhao-Hui Luo¹, Rou-Jie Huang³, Tian Tu¹, Aihua Pan², Ewen Tu⁴, Jim Manavis⁵, Bo Xiao¹, Xiao-Xin Yan²

Affiliations

¹ Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
² Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China.
³ Medical Doctor Program, Xiangya School of Medicine, Central South University, Changsha, China.
⁴ Department of Neurology, Brain Hospital of Hunan Province, Changsha, China.
⁵ Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.

Abstract

Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of SHANK3 are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer's disease (AD)-type β-amyloid (Aβ) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.

Keywords: brain aging; cognitive decline; developmental brain disorders; excitatory neurotransmission; neurodegenerative disorders; neuropsychiatric diseases.