Abstract:
Death rates across the globe, resulting from Alzheimer’s Disease (AD) have nearly tripled in the last 30 years from 1990 to 2023 – ranging from half a million to 1.8 million men and women dying from this debilitating disease respectively. With our aging population, longevity and better health outcomes, the impact of AD is projected to increase exponentially. Whereas, the burden of AD and its outcomes will likely worsen in the underdeveloped countries, people living with compromised socio-economical conditions even in the developed countries, such as the United States (US), are also at high risk. For instance, seniors living in the eastern and southeastern US cities inhabited by a larger Latino and Black American populations are about twice as likely to develop AD as compared with their white American counterparts. It thus stands to reason that a global policy is warranted to tackle this debilitated disease – which will likely be the next pandemic in waiting. The primary targets for drug development in Alzheimer’s Disease (AD) have been the pathologically accumulated amyloid ß (Aß) peptide and tau protein, which form plaques and neurofibrillary tangles, respectively. However, despite significant scientific progress, and the ensuing clinical trials to manage this presumed, causative pathology in the brain, the fundamental mechanisms and the disease management strategies remain elusive. An alternative to Tau and Aß narrative, is the Cholinergic Hypothesis, which implicates the impaired cholinergic synaptic structures and function in the hippocampus underlying learning, memory and cognition. Our lab was the first to demonstrate the role of menin - a protein encoded by the MEN1 tumor suppressor gene, in synapse formation and synaptic plasticity in the hippocampus whereby it targeted and regulated the function of cholinergic receptors underlying learning and memory. Moreover, MEN1 knockdown in a mouse model generates a phenotype analogous to that of AD. We have further demonstrated, for the first time, the presence of menin in both cortex and the hippocampus of autopsied, human AD brain. We found that menin is not only present in the AD brain but also co-localizes with Tau protein in the degenerating neurons. Based on these findings, we propose a novel AD hypothesis that menin and it’s signaling is the missing link regulating the expression of nicotinic acetylcholine receptors in the hippocampus underlying learning, memory and cognition. The experimental evidence will be presented from both the animal models and the human autopsied brain tissues inflicted with AD in support of the MEN1 hypothesis.
Page(s):
DOI:
DOI not available
Published:
Journal: Abstract Book on 9th Annual Neuroscience Conference (ANC-23) August 12-13, 2023 , Volume: 0, Issue: 0, Year: 2023