4.6 Article

Pridopidine Promotes Synaptogenesis and Reduces Spatial Memory Deficits in the Alzheimer's Disease APP/PS1 Mouse Model

Journal

NEUROTHERAPEUTICS
Volume 19, Issue 5, Pages 1566-1587

Publisher

SPRINGER
DOI: 10.1007/s13311-022-01280-1

Keywords

Alzheimer's disease; Neurodegeneration; PRE-084; ACR16; Sigma-1 receptor; Neuroprotection

Funding

  1. Agencia Canaria de Investigacion, Innovacion y Sociedad de la Informacion (ACIISI) of the Regional Consejeria de Economia, Industria y Comercio, Canary Islands Government
  2. European Social Fund [Canarias 2014-2020, Axis 3 Priority Theme 74)
  3. EU [FP7-REGPOT-2012-CT2012-31637-IMBRAIN]
  4. Spanish Ministry of Science and Innovation [PID2019-106509RB-I00]
  5. Department of Integrative Medical Biology, Umea University
  6. Umea University Medical Faculty

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Sigma-1 receptor agonists ACR16 and PRE-084 have been shown to promote the formation of new synapses and dendritic spines in vitro, while also exhibiting neuroprotective effects against oxidative stress and excitotoxicity. In an APP/PS1 mouse model, ACR16 improved spatial learning and memory deficits through activation of the PI3K/Akt pathway.
Sigma-1 receptor agonists have recently gained a great deal of interest due to their anti-amnesic, neuroprotective, and neurorestorative properties. Compounds such as PRE-084 or pridopidine (ACR16) are being studied as a potential treatment against cognitive decline associated with neurodegenerative disease, also to include Alzheimer's disease. Here, we performed in vitro experiments using primary neuronal cell cultures from rats to evaluate the abilities of ACR16 and PRE-084 to induce new synapses and spines formation, analyzing the expression of the possible genes and proteins involved. We additionally examined their neuroprotective properties against neuronal death mediated by oxidative stress and excitotoxicity. Both ACR16 and PRE-084 exhibited a concentration-dependent neuroprotective effect against NMDA- and H2O2-related toxicity, in addition to promoting the formation of new synapses and dendritic spines. However, only ACR16 generated dendritic spines involved in new synapse establishment, maintaining a more expanded activation of MAPK/ERK and PI3K/Akt signaling cascades. Consequently, ACR16 was also evaluated in vivo, and a dose of 1.5 mg/kg/day was administered intraperitoneally in APP/PS1 mice before performing the Morris water maze. ACR16 diminished the spatial learning and memory deficits observed in APP/PS1 transgenic mice via PI3K/Akt pathway activation. These data point to ACR16 as a pharmacological tool to prevent synapse loss and memory deficits associated with Alzheimer's disease, due to its neuroprotective properties against oxidative stress and excitotoxicity, as well as the promotion of new synapses and spines through a mechanism that involves AKT and ERK signaling pathways.

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