How Does Tau Protein Accumulation Harm Brain Cells in Age-Related Neurodegenerative Conditions?
One of the discoveries of past years in Alzheimer's disease research is that the β-amyloid accumulating between cells is less harmful to neurons than other associated proteins involved in the creation of that amyloid. Here is a paper that suggests much the same sort of thing for neurofibillary tangles, the other characteristic form of protein deposit associated with Alzheimer's:
Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood.An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as β-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins.
The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.
These pore-like APF structures, if lodged in the plasma membrane, would prove deadly as the whole point of the membrane is to manage the inputs and outputs to the cell, in this case a neuron.
Another way any insoluble debris in the neuron may cause degeneration is blockage of transport. Our cells have an internal transport system comprising molecular motors that carry vital cargo along a fibre system not unlike a miniature railway. Neurons have long, thin projections (axons) which are particularly vulnerable to transport disruption.
Dr. Pescatore claims to cure Alzheimers by adjusting the Tau protein in the brain. Will you tell me how he does it? Thanks, Herbert