Title : Evidence of the protective effect of allopregnanolone analogues in alzheimer’s disease experimental models
Abstract:
Alzheimer's Disease (AD) is a major cause of cognitive/memory impairment and dementia. Amyloid beta (Aβ) is an extracellular 39-43 residue long peptide whose aggregation is associated with Alzheimer’s disease (AD) and it’s accumulation represents one of the key neuropathological features of AD with the other been hyperphosphorylation of Tau protein which aggregates to form neurofibrillary tangles (NFT). The shift in the Aβ cascade hypothesis from all Aβ to small soluble oligomeric intermediates is directing the search for therapeutics towards the toxic mediators of the disease. Monomeric form of Aβ have been isolated from the brain of AD patients and have in facts been shown to be devoid of neurotoxicity but rather have been suggested to be neuroprotective. The transition of monomers to oligomers serves both as the first event of aggregation and the key event determining the transformation of benign protein to neurotoxic one. Since the pathophysiological mechanisms of AD begin several years before the onset of mild cognitive impairment (MCI) or clinical symptoms, targeting the most toxic oligomers may prove to be an effective treatment by preventing their spread, however for any significant progress to be made in AD therapy, there is urgent need to identify therapeutic agents capable of delaying the onset or slowing down the progression of AD by either destabilizing the oligomeric Aβ forms, preventing the self-assembly of the monomeric Aβ into oligomers and ultimately protecting against the toxic effect of these small soluble Aβ forms. The 5XFAD mice model shows relatively early and aggressive presentation of AD-related phenotype with high intraneuronal Aβ 42 at 1.5 months, memory decline at 1 month and extracellular amyloid deposition at 2 months served as useful tools employed to study the early myelin alteration in AD, how these alterations influence learning and memory and the efficacy of a potential novel therapy in protecting against these early changes. Several methods where combined to evaluate the BR351 (a novel analogue of allopregnanolone) effect on the learning deficit, memory deficit and the capacity of BR351 to protect against Aβ. Single daily dose (10mg/kg) of BR351 prevented memory and learning deficit assessed with Morris water maze, and counteracted the AD induced demylination by preserving Myelin basic protein (MBP) and Proteolipid protein expression in the regions of the hippocampus and corpus callosum. Furthermore, BR351 treatment also prevented AD-evoked decreased neurofilament-200 expression in the regions of the hippocampus and corpus callosum. Thus, these novel analogs may be useful for translational investigations aiming to tackle the early stage of Alzheimer’s.
Audience Take Away
- This research portrays the therapeutic role of neurosteriods neurodegeneration
- Furthermore, it provides pratical and novel analogs that may be useful for translational investigations aiming to tackle the early stage of Alzheimer’s. Additionally, it proposes possible presymptomatic marker for Alzheimer’s disease diagnosis
