SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer’s Disease View Full Text


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Article Info

DATE

2021-11-04

AUTHORS

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

ABSTRACT

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 deficits 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 efficacy 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 profiles 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 efficacious 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 offer a viable strategy to reverse cognitive decline in AD. More... »

PAGES

1-16

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s13311-021-01143-1

    DOI

    http://dx.doi.org/10.1007/s13311-021-01143-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1142397424

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/34738197


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    18 schema:description 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 deficits 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 efficacy 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 profiles 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 efficacious 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 offer a viable strategy to reverse cognitive decline in AD.
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