Headquarters: Kyoto, Japan
Founded: 2022 (Kyoto University spin-out)
Focus: Synaptic protection and repair for Alzheimer's disease
Website: https://www.synaptichealth.co.jp
Synaptic Health Inc. is a Kyoto University spin-out company developing therapeutics that protect and repair synaptic connections in Alzheimer's disease and related dementias. Synapse loss is the strongest pathological correlate of cognitive decline in Alzheimer's disease — more predictive of cognitive impairment than amyloid-beta or tau burden alone[1]. Synaptic Health's approach targets the molecular mechanisms underlying synaptic vulnerability, offering a disease-modifying strategy complementary to amyloid and tau targeting[2].
The company was founded by researchers from Kyoto University's Graduate School of Pharmaceutical Sciences and Graduate School of Medicine who identified novel targets for synaptic protection during a decade of research on the molecular architecture of excitatory synapses.
Synapses are the structural and functional units of neural communication, and their loss is the most significant predictor of cognitive decline in Alzheimer's disease. Post-mortem studies consistently show that the density of dendritic spines — the postsynaptic structures where most excitatory transmission occurs — is dramatically reduced in Alzheimer's disease patients, correlating strongly with ante-mortem cognitive scores[3].
Multiple mechanisms contribute to synaptic loss in Alzheimer's disease:
Synaptic Health has identified three key target pathways for its therapeutic programs:
The NMDA receptor is central to synaptic plasticity, learning, and memory. However, overactivation by amyloid-beta leads to calcium overload and excitotoxicity. Synaptic Health is developing compounds that selectively potentiate synaptic NMDA receptor activity while blocking extrasynaptic NMDA receptor overactivation — a pattern described as "biased agonism"[4].
Postsynaptic density (PSD) proteins including PSD-95, Homer, and Shank family proteins form a signaling scaffold critical for synaptic structure and function[5]. These proteins are targets of proteolysis and misregulation in Alzheimer's disease. Synaptic Health's lead compounds stabilize PSD protein complexes against disease-related degradation.
Synaptotagmins and other vesicle-associated proteins regulate neurotransmitter release probability and plasticity[6]. Synaptic Health is developing modulators that enhance releasable vesicle pools in neurons that have begun to show reduced synaptic output.
Target: PSD-95/Homer complex stabilizer
Stage: Lead optimization
Indication: Alzheimer's disease (early-stage)
SH-201 prevents the disassembly of PSD-95/Homer scaffold complexes that occurs in response to amyloid-beta toxicity. In iPSC-derived neurons from Alzheimer's disease patients, SH-201 treatment preserves spine density and synaptic function despite amyloid-beta exposure.
Target: NMDA receptor synaptic potentiator
Stage: Preclinical (pharmacokinetics optimization)
Indication: Alzheimer's disease, vascular dementia
SH-202 is a biased NMDA receptor modulator that enhances synaptic activity while reducing excitotoxic signaling. The compound has demonstrated cognitive improvement in amyloid-beta injection models and in APP/PS1 transgenic mice.
Synaptic Health's drug discovery approach integrates:
Synaptic Health's work intersects with key mechanisms documented in NeuroWiki:
Spires-Jones TL, et al. Synaptic loss in Alzheimer's disease: mechanisms and consequences. Nature Reviews Neuroscience. 2022. ↩︎
Synaptic Health Inc. Company Profile - Synaptic Protection and Repair. 2024. ↩︎
Coleman JR, et al. Dendritic spine alterations in Alzheimer's disease and related dementias. Acta Neuropathologica. 2023. ↩︎
Buonarati OR, et al. CaMKII signaling at the synapse: from physiology to Alzheimer's disease. Journal of Neuroscience. 2022. ↩︎
Hahn CG, et al. Synaptic scaffolding proteins in neurodegenerative disease. Molecular Psychiatry. 2023. ↩︎
Chapman ER, et al. Synaptotagmins in neurotransmitter release and synaptic plasticity. Current Opinion in Neurobiology. 2021. ↩︎