Longevity medicine is concerned with the avoidance, controlling and reversing of chronic and degenerative diseases, over twenty of which are triggered by misfolded proteins and abnormal amyloids. Below four manifestations of these aberrant proteins.
One of the hallmarks of Alzheimer’s disease is the accumulation of amyloid plaques between nerve cells (neurons) in the brain. Amyloid is a general term for protein fragments that the body produces normally. Beta amyloid is a protein fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these protein fragments are broken down and eliminated. In Alzheimer’s disease, the fragments accumulate to form hard, insoluble plaques.Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space
NEUROFIBRILLARY TANGLES AND TAU PROTEINS
Neurofibrillary tangles are insoluble twisted fibers found inside the brain’s cells. These tangles consist primarily of a protein called tau, which forms part of a structure called a microtubule. The microtubule helps transport nutrients and other important substances from one part of the nerve cell to another. In Alzheimer’s disease, however, the tau protein is abnormal and the microtubule structures collapse.
Amyloid fibrils are peptide or protein aggregates that form under certain conditions. For example, the amyloid fibril plaques found in brain tissue of Alzheimer patients are formed from the peptide Aβ and are associated with neurodegeneration. Abnormal amyloids have been associated with the pathology of more than 20 serious human diseases including, but not limited to Huntington, Parkinson and Alzheimer’s diseases as well as Rheumatoid arthritis, artherosclorosis, Type 2 Diabetes and senile systemic amyloidosis. Amyloid fibrils are extremely stable and resistant to degradation. They have been described as having a similar tensile strength to steel,75 a property that they share with their structural cousin, silk.
An abundance of evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Aβ peptide, but the precise mechanism of pathogenicity remains to be established. Amyloids grow into long, thin fibrils by the addition of misfolded proteins on to the ends. Proteins are linear strands of amino acids that fold into complex globular shapes that are critical for the proteins function. In order for a normal protein to form an amyloid fibril, it must undergo a change in its original shape from a globular form to an unwound abnormal shape that allows it’s self-assembly with other misfolded protein strands, like dominos. This assembly can go on infinitely, so that each amyloid fibril may contain a million or more individual subunits or blocks.
Although amyloid accumulation is a key feature of AD, it also presented an enigma because the accumulation of insoluble amyloid fibril deposits is poorly correlated with dementia. Some cognitively normal individuals were found to have the same amount of insoluble amyloid deposits as AD patients, indicating that these deposits are not always associated with disease. Similarly, other AD patients have been observed with relatively little of the insoluble amyloid deposits. These observations refocused research away from the insoluble amyloid deposits to other types of amyloid aggregates known as “oligomers”.
More recent research in amyloid aggregation has discovered that the amyloid formation pathway also includes smaller aggregates, or oligomers and these oligomers have a different shape or conformation of the protein than that found in amyloid fibrils. In this realm, the oligomer conformation does not co-assemble with the fibril building blocks, but rather only supports the self-assembly of small aggregates of about 3-24 individual peptide strands.
Amyloid oligomers have been observed for AD and other amyloid-related degenerative diseases. There is increasing evidence that these small oligomers, rather than the long fibrils, are the primary toxic or pathogenic species that cause all of these degenerative diseases. In other words, oligomers are more toxic to cells and their presence correlates better with disease than the fibrils. Determination of the structures of these toxic oligomers, what they do to cause disease and how we may prevent their toxic activity are presently objects of scientific inquiry including at the Optimal Longevity Institute.
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