Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor

NEUROBIOLOGY OF DISEASE

卷:124

Article

Ryskamp, Daniel¹  Wu, Lili¹  Wu, Jun¹  Kim, Dabin²  Rammes, Gerhard²  Geva, Michal^3,5  Hayden, Michael^3,5  Bezprozvanny, Ilya^1,4 

[1] Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA

[2] Tech Univ Munich, Dept Anesthesiol & Intens Care, D-81675 Munich, Germany

[3] Prilenia Therapeut, Herzliyya, Israel

[4] Peter Great St Petersburg Polytech Univ, Lab Mol Neurodegenerat, St Petersburg, Russia

[5] Teva Pharmaceut Ind Ltd, 5 Basel St, IL-49131 Petah Tiqwa, Israel

关键词: 3-PPP;    Alzheimer's disease;    APP knock-in mice;    Calcium dysregulation;    Mushroom spines;    Presenilin-1-M146 V knock-in mice;    Pridopidine;    Sigma-1 receptor;    Synaptic instability;    Synaptoprotection;   

DOI  :  10.1016/j.nbd.2018.12.022

来源: Elsevier

【 摘 要 】

There is evidence that cognitive decline in Alzheimer's disease (AD) results from deficiencies in synaptic communication (e.g., loss of mushroom-shaped 'memory spines') and neurodegenerative processes. This might be treated with sigma-1 receptor (S1R) agonists, which are broadly neuroprotective and modulate synaptic plasticity. For example, we previously found that the mixed muscarinic/S1R agonist AF710B prevents mushroom spine loss in hippocampal cultures from APP knock-in (APP-KI) and presenilin-1-M146 V knock-in (PS1-KI) mice. We also found that the dopaminergic stabilizer pridopidine (structurally similar to the S1R agonist R(+)-3-PPP), is a high-affinity S1R agonist and is synaptoprotective in a mouse model of Huntington disease. Here we tested whether pridopidine and R( +)-3-PPP are synaptoprotective in models of AD and whether this requires S1R. We also examined the effects of pridopidine on long-term potentiation (LTP), endoplasmic reticulum calcium and neuronal store-operated calcium entry (nSOC) in spines, all of which are dysregulated in AD, contributing to synaptic pathology. We report here that pridopidine and 3-PPP protect mushroom spines from A beta(42) oligomer toxicity in primary WT hippocampal cultures from mice. Pridopidine also reversed LTP defects in hippocampal slices resulting from application of A beta(42) oligomers. Pridopidine and 3-PPP rescued mushroom spines in hippocampal cultures from APP-KI and PS1-KI mice. S1R knockdown from lenti-viral shRNA expression destabilized WT mushroom spines and prevented the synaptoprotective effects of pridopidine in PST-K1 cultures. Knockout of PS1/2 destabilized mushroom spines and pridopidine was unable to prevent this. Pridopidine lowered endoplasmic reticulum calcium levels in WT, PST-KO, PST-KI and PS2 KO neurons, but not in PS1/2 KO neurons. S1R was required for pridopidine to enhance spine nSOC in PS1-KI neurons. Pridopidine was unable to rescue PS1-KI mushroom spines during pharmacological or genetic inhibition of nSOC. Oral pridopidine treatment rescued mushroom spines in vivo in aged PS1-KI-GFP mice. Pridopidine stabilizes mushroom spines in mouse models of AD and this requires S1R, endoplasmic reticulum calcium leakage through PS1/2 and nSOC. Thus, pridopidine may be useful to explore for the treatment of AD.

【 授权许可】

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