Derivatives of Piperazines as Potential Therapeutic Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that is the major cause of dementia in the elderly. There is no cure against AD. We have recently discovered a novel transient receptor potential canonical 6 (TRPC6)-mediated intracellular signaling pathway that regulates the stability of dendritic spines and plays a role in memory formation. We have previously shown that TRPC6 agonists exert beneficial effects in models of AD and may serve as lead compounds for development of AD therapeutic agents. In the current study, we used the Clarivate Analytics Integrity database to search for additional TRPC6 agonists. We selected four compounds to study as potential neuroprotective agents. We applied bioinformatics analyses to test the basic pharmacological properties of the selected compounds. We performed in vitro screening of these compounds to validate their ability to protect mushroom spines from amyloid toxicity and determined that two of these compounds exert neuroprotective effects in the nanomolar concentration range. We have chosen one of these compounds [piperazine (PPZ)] for further testing. In agreement with previously published data, we have shown that PPZ potentiates TRPC6 channels. We demonstrated that the neuroprotective mechanism of the investigated PPZ is based on activation of neuronal store-operated calcium entry in spines. We have shown that PPZ restores long-term potentiation induction in 6-month-old 5xFAD mouse hippocampal slices. The obtained results suggest that PPZ and its derivatives are potential lead molecules for development of AD therapeutic agents.

Dysregulation of neuronal calcium homeostasis in Alzheimer's disease - A therapeutic opportunity?

Alzheimer's disease (AD) is the disease of lost memories. Synaptic loss is a major reason for memory defects in AD. Signaling pathways involved in memory loss in AD are under intense investigation. The role of deranged neuronal calcium (Ca2+) signaling in synaptic loss in AD is described in this review. Familial AD (FAD) mutations in presenilins are linked directly with synaptic Ca2+ signaling abnormalities, most likely by affecting endoplasmic reticulum (ER) Ca2+ leak function of presenilins. Excessive ER Ca2+ release via type 2 ryanodine receptors (RyanR2) is observed in AD spines due to increase in expression and function of RyanR2. Store-operated Ca2+ entry (nSOC) pathway is disrupted in AD spines due to downregulation of STIM2 protein. Because of these Ca2+ signaling abnormalities, a balance in activities of Ca2+-calmodulin-dependent kinase II (CaMKII) and Ca2+-dependent phosphatase calcineurin (CaN) is shifted at the synapse, tilting a balance between long-term potentiation (LTP) and long-term depression (LTD) synaptic mechanisms. As a result, synapses are weakened and eliminated in AD brains by LTD mechanism, causing memory loss. Targeting synaptic calcium signaling pathways offers opportunity for development of AD therapeutic agents.