The infamous protein clumps found in Alzheimer's patients may be a harmless side effect rather than the actual cause of brain damage.
Scientists have spent decades trying to dissolve the large filaments of Tau protein that aggregate in diseased brains. Neurodegeneration is actually driven by a specific part of the protein called the 306VQIVYK311 domain before it ever forms a clump. This tiny sequence becomes toxic when it undergoes a chemical change called phosphorylation. The large aggregates might even be the body's way of trying to hide these toxic fragments away. Shifting focus away from the visible clumps toward these early chemical changes could finally lead to effective treatments for dementia.
Tau toxicity is gated through the 306VQIVYK311 domain but through mechanisms not entirely dependent on Tau aggregation
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Abstract Disease-modifying therapies for Tauopathies like Alzheimer’s disease have targeted Tau hyperphosphorylation and aggregation, as both pathological manifestations are implicated in Tau-mediated toxicity. More recently there has been a renewed interest in Tau conformation which appears to influence its toxic potential. However, the impact of Tau hyper-phosphorylation on its eventual conformation and toxic potential is less well known. Leveraging the genetic tractability of Drosophila , we