(Georgia Institute of Technology, 2017-05)
Huber, Colin Michael
Alzheimer’s Disease (AD) pathology is characterized by the accumulation of extracellular amyloid-β (Aβ) plaques in the brain followed by growth of phosphorylated tau (pTau) proteins into neurofibrillary tangles (NFTs). Both Aβ plaques and NFTs interfere with normal neuronal cell function by disrupting proper synaptic signaling and inflicting damage to neurons, eliciting cognitive decline. The presence of Aβ coincides with a decrease in cognitive performance; however, quantified Aβ accumulation does not correlate with cognitive decline. There have been no FDA-approved drugs capable of curing AD or delaying disease progression with research efforts heavily focused on amyloid-β as the primary causative agent in AD pathology. We performed a meta-analysis examining research studies matching inclusion criteria extracted from a database of more than 3,000 Alzheimer’s mouse model peer-reviewed articles. Phosphorylated tau, total tau, and amyloid-β levels were compared to measure the largest impact on cognitive performance by correlative assessment with Morris water maze escape latency and Novel Object Recognition. Phosphorylated tau accumulation into NFTs more strongly correlates with cognitive decline than Aβ despite a smaller total concentration, and therefore, pTau may contribute more to Alzheimer’s Disease progression. The two proteins interact through GSK3β and other phosphorylation pathways causing more rapid cognitive decline, and the onset of Aβ leads to the development of NFTs. Aβ and tau pathologies are interwoven in a complex manner that prevents separation. Alzheimer’s disease treatment will require the removal of both protein accumulation, and research should focus on combination drugs and defining the connection between Aβ and pTau.