A positive modulator of AMPA receptors against AD pathology: in vivo studies

• Author(s): Fernandes, Daniela Monteiro
• Date: 2018
• Persistent ID: https://hdl.handle.net/1822/81872
• Origin: RepositóriUM - Universidade do Minho
• Document Type: Master thesis
• Language: English
• Contributor(s): Universidade do Minho; Sotiropoulos, I.

Description

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder among the elderly, estimated to affect approximately 47 million people worldwide, a number that is expected to triple in just 3 decades. While the currently available drugs only temporarily improve memory and cognitive function or delay the progression of dementia, there is no effective cure at the moment with AD remaining a devastating disorder with unclear initiators. Clinical evidence suggests that stressful life events can be a risk factor for AD while recently, depression, another stress-related disorder, is also shown to predispose to AD. Experimental evidence supports stress as the pathological link between depression and AD, as stress and main stress hormones, glucocorticoids, trigger the two AD pathomechanisms, A overproduction and Tau hyperphosphorylation; both trigger neuronal malfunction and loss with glutamate excitotoxicity having an essential role in AD neuropathology. Based on the above, this Master thesis investigates the potential therapeutic action of S 47445, a positive allosteric modulator of AMPA receptors, against Ab-driven AD pathology using two experimental set-ups: i) Aβ oligomers hippocampal injection followed by acute administration of the S47445 compound and, ii) combined chronic stress/Aβ1-40-infusion model. Our findings demonstrate that S 47445 compound reverted different short- and long-term memory deficits found in our AD model, suggesting a beneficial effect of hippocampus- and prefrontal-cortex-dependent function. Indeed, S 47445 was able to ameliorate the spatial and reference memory deficits found upon hippocampal injection of Aβ oligomers and to revert the recognition and spatial reference memory impairments in the stress/Aβ1-40-infusion model. Notably, S 47445 protective action was specific to the modulation of the cognitive dimension of behavioral deficits in of this AD model, as it exhibited no positive impact on mood deficits (lack of anxiolytic or anti-depressive effects). These studies constitute the first in vivo evidence of the potential therapeutic benefit of S 47445, targeting AMPA receptors and their signaling against AD pathology.