Ponderments of the brain.

Alzheimers was not a word used in instances of "senile dementia" situations until more recent decades as it had been supposed such dementia was not so much a distinct disease but rather a matter of aging (albeit age remains a factor). However, now the term is also used in situations of non early onset and the diagnosis is validated by both clinical findings of behavior as well as amyloid plaques and neurofibrillary tangles. Futhermore, while "normal" persons (no behavioral disturbances) may have these same findings of amyloid plaques and neurofibrillary tangles, it may be a matter of degree especially of neurofibrillary tangles (as number of plaques are not necessarily indicative of degree of apparent dementia as evidenced by behavior). While past treatments have been aimed at reducing the amyloid plaques, this may have been misdirected. Amyloid plaques are extracellular whilst neurofibrillary tangles are intracellular. It is thought the the amyloid-beta peptide 42(a soluble protein) may be the major or causative element in the neurodegenerative process . Either too much amyloid-beta 42 is made or not cleared away. When too much is present, the individual little peptides stick together and cause oligomers. These gluey oligomers of amyloid-beta 42 lodge in synapses between neurons and interfere with synaptic transmission. Eventually the neurons atrophy from non-use and/or inflammation. Possibly the heap of amyloid-beta (e.g. 40 and 42) results in the plaques. Beta-amyloid gets released when the amyloid precursor protein (APP)* on a brain cell is cut by two enzymes: Beta-secretase and gamma-secretase. (A third enzyme that snips it, alpha-secretase, actually prevents Alzheimer's-related plaques from forming). (*APP is best known as the precursor molecule whose proteolysis** (**i.e. breakdown of protein into smaller units) generates beta amyloid 37 to 49 peptides whose amyloid fibrillar form is the primary component of amyloid plaques as found in Alzheimer). The secretase can cut APP at several points within a small region of the protein which results in alpha beta of various lengths. The length associated with Alzheimer's are 40 and 42 amino acids long. Alpha beta 42 is more likely to aggregate. In the less common heredity type of Alzheimers (fn A), it has been found that mutations found in presenilin* (*subcomponent of gamma secretase (multi pass transmembrane protein that functions as part of gamma secretase)) lead to an increase in the ratio of alpha beta 42 produced compared to Alpha Beta 40, albeit total quantity of alpha beta remains constant. As for Alzheimers in general, Aβ, which are unstructured in the monomeric state, go on to form characteristic beta-hairpin like structures in the fibrillar aggregates through a ‘misfolding’ step. On the way of transition from the monomeric peptide to fibrils* (*abnormal protein assembly) Aβ forms a wide variety of species of different sizes and some of them are related to the toxicity. The hairpin like ‘misfolding’ of the peptide seems to a critical phenomenon for the aggregation and may also be strongly related to the toxicity. When does this misfolding occur? A study of the lifetime of the fluorophore reports the end to end distance of this peptide in the monomeric as well as in the aggregated state reveals a major conformational transition between the monomer/small oligomer species (~1nm) and the larger oligomeric species (>2 nm) This perspective as to how Alzheimers may be initiated (and thus possibly prevented) appears circumstantially expressed by findings in the Nature study (2012) which suggest that when people have a newly discovered mutation on the APP gene, they naturally experience less cutting from beta-secretase, resulting in lower amounts of beta-amyloid getting into the brain from birth thus providing apparent protection from Alzheimers. (albeit this mutation has only thus far been found in Iceland) It is now believed that certain misfolded oligomers (known as seeds)can induce other amyloid beta molecules to take misfolded oligomer form, leading to a chain reaction akin to prion infection. There is some evidence the misfiled amyloid beta can induce tau to misfold as well. Such may result in the inception of toxic protein species due to nonproductive templating (e.g. where the substrate exceeds amyloid conversion or if amino acid sequences are incompatible) and such may give rise to abnormal conformation of species that may go on to form toxic oligomers (e.g. soluble oligomer of the amyloid-beta peptide 42) and amorphous aggregates. Prefibrillar oligomers may disassemble tau dependent microtubules (resulting in the neurofibrillary tangles) and thus may cause and or contribute to the disruption of axonal transport (i.e. specific oligomeric form of amyloid-beta (esp # 42) is a trigger for loss of synapses and neuronal damage) Questions remain as to whether the over expression of the precursor protein (APP) is sufficient to cause pathology. Thus the thinking is changing to that it may be the poorly defined pre-amyloid species rather than the plaques that are the true toxic conformations. The subsequent amyloid plagues themselves also seem to be a protection against Alzheimer's. More recent studies have found that these plaques as well as inclusion bodies may circumvent the formation of more toxic species such as pre fibrillar oligomers and thus are actually a reaction and/or protection devise as opposed to pathogenic: plaque formation being an attempt to protect cells from the effect of toxic misfolded proteins. Rather than cellular dysfunction and neuronal loss itself, amyloid plaques may be the product of a cellular process enabling cells to cope with the accumulation of misfolded and damaged proteins. It is suggested that the plaques and inclusion bodies may become inefficient from accumulating protein damage. (Much still needs to be understood but long past are the days when researchers peered into the brains that had evidenced dementia and found mysterious items...and pondered....were they alive? Past researchers pondered whether the mysterious findings were of fungal nature (mycotic?)). Much more is known now; much more needs to be gleaned. Interesting studies show for example that small poisonous Aβ assemblies, called oligomers, bind strongly to vulnerable neurons in the brain, but in the presence of collagen VI, this binding was blocked. Studies showed that collagen VI and Aβ form large aggregates with each other that may sequester the smaller, more toxic Aβ complexes away from neurons. Important clues such as the presence/effect of collagen VI (made in the brain itself!) provide possible solutions against AD. Also some researchers have found that the Aβ oligomers induce some of the symptoms of Alzheimer's Disease by competing with insulin for binding sites on the insulin receptor, thus impairing glucose metabolism in the brain. There are also studies regarding the positive effect of acid DHA in relation to alzheimers. Also another approach is one by Biogen which is researching an antibody called "adu" which appears to target amyloid protein and which has shown some evidence of promise in patients with mild and even incipient Alzheimers (evidenced by clinical findings (e.g. cognitive tests) as well as by emerging technology of imaging equipment that allows clinicians to pin point amyloid deposits and tau in the brain) (Aducanumab antibody derived from elderly patients in Switzerland who were especially mentally quick and healthy). So fingers are crossed and one can be cautiously optimistic for the future. A new avenue of study regards C1q which is a protein that normally does synaptic pruning (essential for the brain) but if in conjunction with the toxic soluble Aβ, it may cause synaptic destruction. Fn A(Re hereditary alzheimers, dominant mutations in genes that encode presenilin proteins are the most common cause of familial early onset Alzheimers)