Novel approaches to increase synaptic resilience as potential treatments for Alzheimer's disease

Semin Cell Dev Biol. 2023 Apr;139:84-92. doi: 10.1016/j.semcdb.2022.03.032. Epub 2022 Mar 31.

Abstract

A significant proportion of brains with Alzheimer's disease pathology are obtained from patients that were cognitively normal, suggesting that differences within the brains of these individuals made them resilient to the disease. Here, we describe recent approaches that specifically increase synaptic resilience, as loss of synapses is considered to be the first change in the brains of Alzheimer's patients. We start by discussing studies showing benefit from increased expression of neurotrophic factors and protective genes. Methods that effectively make dendritic spines stronger, specifically by acting through actin network proteins, scaffolding proteins and inhibition of phosphatases are described next. Importantly, the therapeutic strategies presented in this review tackle Alzheimer's disease not by targeting plaques and tangles, but instead by making synapses resilient to the pathology associated with Alzheimer's disease, which has tremendous potential.

Keywords: AD model mice; APOE2, Klotho; APP/PS1; Neuroprotection; PSD-95, phosphatases, cofilin, calcineurin, BDNF; Therapeutic strategies.

Publication types

  • Review

MeSH terms

  • Actins / metabolism
  • Alzheimer Disease* / genetics
  • Animals
  • Brain / metabolism
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Synapses / metabolism

Substances

  • Actins