Postsynaptic Protein Shank3a Deficiency Synergizes with Alzheimer’s Disease Neuropathology to Impair Cognitive Performance in the 3xTg-AD Murine Model

Olivier Landry, Arnaud François, Méryl Farelle Oye Mintsa Mi-Mba, Marie Therese Traversy, Cyntia Tremblay, Vincent Emond, David A. Bennett, Karen H. Gylys, Joseph D. Buxbaum, Frédéric Calon

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Synaptic loss is intrinsically linked to Alzheimer’s disease (AD) neuropathology and symptoms, but its direct impact on clinical symptoms remains elusive. The postsynaptic protein Shank3 (SH3 and multiple ankyrin repeat domains) is of particular interest, as the loss of a single allele of the SHANK3 gene is sufficient to cause profound cognitive symptoms in children. We thus sought to determine whether a SHANK3 deficiency could contribute to the emergence or worsening of AD symptoms and neuropathology. We first found a 30%-50% postmortem loss of SHANK3a associated with cognitive decline in the parietal cortex of individuals with AD. To further probe the role of SHANK3 in AD, we crossed male and female 3xTg-AD mice modelling Ab and tau pathologies with Shank3a-deficient mice (Shank3Dex4-9). We observed synergistic deleterious effects of Shank3a deficiency and AD neuropathology on object recognition memory at 9, 12, and 18months of age and on anxious behavior at 9 and 12months of age in hemizygous Shank3Dex4-9-3xTg-AD mice. In addition to the expected 50% loss of Shank3a, levels of other synaptic proteins, such as PSD-95, drebrin, and homer1, remained unchanged in the parietotemporal cortex of hemizygous Shank3Dex4-9 animals. However, Shank3a deficiency increased the levels of soluble Ab42 and human tau at 18months of age compared with 3xTg-AD mice with normal Shank3 expression. The results of this study in human brain samples and in transgenic mice are consistent with the hypothesis that Shank3 deficiency makes a key contribution to cognitive impairment in AD.

Original languageEnglish
Pages (from-to)4941-4954
Number of pages14
JournalJournal of Neuroscience
Volume43
Issue number26
DOIs
StatePublished - 28 Jun 2023

Keywords

  • Alzheimer’s disease
  • Shank3
  • aging
  • mouse model
  • neurodegenerative disease
  • synaptic plasticity

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