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

Abstract

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-M146V 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, both of which are dysregulated in AD, contributing to synaptic pathology. We report here that pridopidine and 3-PPP protect mushroom spines from Aβ 42 oligomer toxicity in primary WT *

Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease

“…In previous experiments we demonstrated various effects which were mediated by the S1R, and potent at the range of 100 nM–1 μM. These effects include upregulation of the BDNF pathway (Geva et al, 2016), rescue of spines and calcium homeostasis (Ryskamp et al, 2017, 2019), and enhancement of axonal BDNF transport (Ionescu et al, 2019). In addition, these concentrations correlate to the drug brain exposure levels of pridopidine used in clinical trials (Geva, unpublished data).…”

Therapeutic Advances for Huntington’s Disease

“…Pridopidine is a modulator of the dopamine 2 receptor [130] and activates the sigma-1 receptor [131]. In the most recent trials of pridopidine, no improvement in motor symptoms (unified Huntington's Disease rating scale -total motor score (UHDRS-TMS)) was observed with placebo [132][133][134].…”

Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in cellular and Drosophila ALS/FTD models

“…The Sig-1R 16 – 25 is a ligand-regulated molecular chaperone that resides mainly at the mitochondria-endoplasmic reticulum (ER) interface, referred to as the mitochondria-associated ER membrane (MAM), where it chaperones IP3R3 to ensure proper Ca 2+ signaling from the endoplasmic reticulum into mitochondria 26 , 27 . The Sig-1R exists at other parts of cell as well and has been proposed to be an important protein for cellular survival 28 – 34 as a dynamic pluripotent modulator in living systems 35 .…”