RT Journal Article
T1 SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer's Disease
A1 Trujillo-Estrada, Laura Isabel
A1 Vanderklish, Peter
A1 Minh Thu Nguyen, Marie
A1 Kuang, Run Rong
A1 Nguyen, Caroline
A1 Huynh, Eric
A1 da Cunha, Celia
A1 Ibarra Javonillo, Dominic
A1 Forner, Stefania
A1 Martini, Alessandra C.
A1 Sarraf, Stella
A1 Simmon, Vicent
A1 Baglietto-Vargas, David
A1 LaFerla, Frank
K1 Alzheimer, Enfermedad de
AB Alzheimer’s disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive defcits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efcacy of a novel synaptogenic small molecule, SPG302 — a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses — in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins — including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) — and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efcacious in this model without modifying Aβ and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density ofer a viable strategy to reverse cognitive decline in AD.
PB Elsevier
YR 2021
FD 2021-10
LK https://hdl.handle.net/10630/32646
UL https://hdl.handle.net/10630/32646
LA spa
NO Laura Trujillo-Estrada, Peter W. Vanderklish, Marie Minh Thu Nguyen, Run Rong Kuang, Caroline Nguyen, Eric Huynh, Celia da Cunha, Dominic Ibarra Javonillo, Stefania Forner, Alessandra C. Martini, Stella T. Sarraf, Vincent F. Simmon, David Baglietto-Vargas, Frank M. LaFerla, SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer's Disease, Neurotherapeutics, Volume 18, Issue 4, 2021, Pages 2468-2483, ISSN 1878-7479, https://doi.org/10.1007/s13311-021-01143-1. (https://www.sciencedirect.com/science/article/pii/S1878747923007171)
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 20 ene 2026