Novel treatment of dementia-associated tauopathies
One of the main causes of dependency and disability among the elderly worldwide is dementia. In 60-70% of the cases, the underlying condition of dementia is Alzheimer’s disease (AD), most frequently tauopathy. At present, only 5 medications for the treatment of AD are approved, all of which treat symptoms. The mechanism of pathogenicity in tauopathies has been shown to be the hyperphoshorylation of Tau protein which in turn results in the formation of Tau tangles in nerve cells and leads to network malfunctions and neuronal death. The challenge is to target the pathogenic mechanism pharmaceutically.
Impact of 5-HT7R inverse agonist on Tau-mediated pathology.
Candidate molecules are serotonin 5-HT7 receptor inverse agonists for use in preventing or treating tauopathies. The inverse agonist prevents hyperphosphorylation of the Tau protein (p-Tau). In the neuroblastoma cell line model expressing mutated human Tau, an inverse agonist reversed accumulation of Tau, p-Tau and Tau aggregates. Immunfluorescence confirmed the prevention of Tau aggregates formation. Blockade of constitutive receptor activity in neurons that overexpressed pathological Tau prevented Tau hyperphosphorylation, aggregation, and neurotoxicity. Moreover, receptor knockdown in prefrontal cortex fully abrogated Tau-induced deficits in long term potentiation and memory impairments. Application of approved drugs possessing inverse agonism towards the 5-HT7R demonstrate similar favorable effects both in vitro and in vivo.
Licensing and/or co-development.
In vivo data. Preclinical development.
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