Basil Alias and Ian Murray

Introduction. Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by the degradation and atrophy of the neural tissue of the brain leading to neurological issues such as memory loss^1,2. Over 35% of people over the age of 85 in the United States have AD^1,2. Currently, AD progression is determined by neurological testing, but new research is focusing on neuronal proteins. One such protein, Tau, are soluble intracellular protein involved in the stability of microtubules in neurons. However,  once phosphorylated and misfolded, they form insoluble neurofibrillary tangles (NFTs) that aggregate and spread from neuron to neuron^3,4. The misfolding, spread, and accumulation of these aggregates precede gray matter loss in regions that correlate to neurological deficits in patients suffering from AD^3,4. Methods. Through multiple mechanisms, tau proteins are phosphorylated, detach from microtubules and misfold. Pathological tau is shown to spread through the limbic network^4,5and there are several mechanisms of cell-to-cell tau seeding.  The two exosome mechanisms include (1) Cholesterol/ Sphingomyelin/PI(4,5)P2 microdomains, and (2) binding on heparan sulfate proteoglycans (HSP)⁶. Using the protein markers GFP-tau441, LAMP1, and intraneuronal fluorescence recovery after photobleaching, the aggregation of tau-proteins was observed in the cytosol of neurons³. This phenomenon was also observed with 4 pro-aggregation mutants for tau (tau441 p301L, tau441 P301S, k280, tau441 A152T)³. In another study, the spread of tau was simulated using epidemic spreading computer models (ESM) and correlated with MRI images of pathological spread controlling for β-amyloid⁴. Results. Changes in phosphorylated tau structure and electrostatic interactions are key for droplet formation³ promoting spontaneous liquid-liquid phase separation and tau droplet formation at lower physiological concentrations. These localized areas of concentrated pathological tau create favorable conditions to form NFTs. The ESM study indicated that tau spreads from neuron to neuron through the limbic system, similar to neuronal spreading proposed by Braak and Braak^4,7. Additionally, the spread of tau was accelerated in brain regions with misfolded extracellular β-amyloid⁴. Conclusions. There is a significant correlation between phosphorylated tau protein/NFTs, its transcellular movement, and the progression of AD^3,4,8,9. Extracellular interactions with tau enable favorable conditions for droplet formation, accelerating misfolding and aggregation of tau. These extracellular interactions likely occur during the exosome-based transcellular spread of tau proteins. This mechanism may provide potential targets for AD treatment and may be used to predict cognitive change and disease progression in an AD patient’s brain.

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