detalle del documento
IDENTIFICACIÓN

oai:pubmedcentral.nih.gov:1031...

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

Society for Neuroscience

Categoría

The Journal of Neuroscience

Año

2023

fecha de cotización

5/7/2023

Palabras clave
synaptic 3xtg-ad δex4-9 brain human levels months disease alzheimer age shank3 shank3a mice ad cognitive neuropathology symptoms
Métrico

Resumen

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 Aβ and tau pathologies with Shank3a-deficient mice (Shank3(Δex4-9)).

We observed synergistic deleterious effects of Shank3a deficiency and AD neuropathology on object recognition memory at 9, 12, and 18 months of age and on anxious behavior at 9 and 12 months of age in hemizygous Shank3(Δex4-9)-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 Shank3(Δex4-9) animals.

However, Shank3a deficiency increased the levels of soluble Aβ(42) and human tau at 18 months 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.

SIGNIFICANCE STATEMENT Although the loss of several synaptic proteins has been described in Alzheimer's disease (AD), it remains unclear whether their reduction contributes to clinical symptoms.

The results of this study in human samples show lower levels of SHANK3a in AD brain, correlating with cognitive decline.

Data gathered in a novel transgenic mouse suggest that Shank3a deficiency synergizes with AD neuropathology to induce cognitive impairment, consistent with a causal role in AD.

Therefore, treatment aiming at preserving Shank3 in the aging brain may be beneficial to prevent AD.

Landry, Olivier,François, Arnaud,Oye Mintsa Mi-Mba, Méryl-Farelle,Traversy, Marie-Therese,Tremblay, Cyntia,Emond, Vincent,Bennett, David A.,Gylys, Karen H.,Buxbaum, Joseph D.,Calon, Frédéric, 2023, Postsynaptic Protein Shank3a Deficiency Synergizes with Alzheimer's Disease Neuropathology to Impair Cognitive Performance in the 3xTg-AD Murine Model, Society for Neuroscience

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