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Dementia

There exist various types of dementia, but predominant form is of Alzheimer¡¯s type followed by frontotemporal lobal dementia of chromosome17 and Lowy body dementia. The disease is not only related to amnesia, but accompanies erratic behaviors such as depression, manic behavior, schizophrenia, coordination, sensory delusion and many behavioral disorder. The histochemistry and pathology of the disease varies according to the characteristic structure of the damaged brain area, but the hallmark is manifested by amyloid beta plaques and neurofibrillary tangle (NFT). Figure 3 Pathological markers of Alzheimer¡¯s disease are characteristic exhibition of amyloid-beta plaques and neurofibrillary tangles Beta-amyloid has been substantially accumulated along with calcium and glutamate in the brain of patients of Alzheimer¡¯s disease. Beta-amyloid, particularly amyloid-beta42, is a peptide consisting of 42 amino acids degraded by both beta- and gamma-secretase from amyloid precursor protein, and subsequently forming a plaque resulting from H-bond and deposited at extracellular wall. Intracellular neurofibrillary tangle (NFT) is also a hallmark of Alzheimer¡¯s dementia. NTF results from hyperphosphorylation of tau and MAPs (microtubule associated proteins). Amyloid beta structure is soluble in membrane lipid, which makes it possible to diffuse in the inside of the neuron. Once considered inert, Abeta-42 is toxic to other neurons. At the same time, paired helical filament (PHF), an immature form of NTF, is a deadly toxic form (see Figure 2). The blood flows at a rate of 1 liter/minute to brain, and the glucose consumption of the brain is about 25% of total glucose consumption of the body. The weight of brain is about 2% of the total weight of brain. The brain must work so hard. If something is wrong with the brain, the whole thing would be screwed up. Streaming flow of blood to the brain warrants the health of the brain. Otherwise, there will be a massive brain cell death which eventually ends up with stroke and/or vascular dementia. Clinical symptom begins to develop usually at the age 65 and half of the people above 85 of age suffer from Alzheimer¡¯s disease. But it is a disease that can be cured using proper therapeutic intervention and changing life style. Society enters period of longevity and Alzheimer¡¯s disease becomes a subject of intensive research and readjustment of social structure. Etiology of Alzheimer¡¯s disease is rather narrowly focused. Patients born of Down¡¯s syndrome suffer from Alzheimer¡¯s symptom at early age of 40, and babies of fetal alcohol syndrome (FAS) and fetal tobacco syndrome (FTS) develop Alzheimer¡¯s symptom at early age. Babies of pregnant women under chronic stress are susceptible to early development of Alzheimer¡¯s disease. One of the most horrifying phenomena is that Alzheimer¡¯s disease occurs at younger age with time.     Alzheimer¡¯s disease can also be traced from the previously existing condition such as diabetes, stroke, and fully integrated with immune and hormone systems. Tau is a microtubule associated protein (MAP) expressed in entire central nervous system and localized in axon from which the name of the VIAXON research institution originates, namely via axon). Partially phosphorylated Tau in normal person has a sequence motif stabilizing tubulin, but hyperphosphorylation destabilizes microtubule. The longest isoform of Tau has 79 serine and threonine residues, 30 of which are phosphorylated under normal condition. However, hyperphosphorylation, tangle formation, and paired helical filament (PHF) are a typical manifestation of Alzheimer¡¯s disease. Both amyloid plaques and NFT result from misfolding of deformed or denatured proteins. Figure 4 PHF(Paired helical filament) In the brain tissue of Alzheimer¡¯s patients, markers of oxidative injury are observed. It is due to oxidative stress activating Jnk (Jun kinase) signal pathway. Tau-induced neurodegeneration is related to Jnk activation and oxidative stress is the cause of Tau-induced neurodegeneration. Oxidative stress is causing irregular aerobic metabolism and is a threat to neuronal homeostasis. Brain is very susceptible to oxidative injury because brain cell membrane is made of lipid easily oxidized upon oxidative stress. Another evidence is that ectopically expressed cell cycle markers are found in Alzheimer¡¯s patients. Aberrant activation of cell cycle causes neurodegeneration. It is not clear that oxidative stress causes cell cycle activation. A-42 and Tau Pathological hallmarks of Alzheimer¡¯s disease are plaque formation of amyloid beta-42 peptide by beta-sheet hydrogen bond at the extracellular membrane and tangled deposit of neurofibril which results from hyperphosphorylation of Tau and microtubule-associated proteins (MAPs). The Abeta-42 plaque is not toxic in its insoluble solid form, but it becomes soluble in membrane lipid interface, diffuse into the cell membrane and exhibits toxicity and kills neighboring neurons like infectious disease. Abeta-42 monomer, a premature form of the plaque, is in equilibrium with polymeric form. In a similar way, the neurofibrillary tangle (NFT) is not toxic in a solid aggregate state, but its immature form called Paired Helical Filament (Figure 2) is known to be toxic. These two seemingly unrelated pathological events are closely related because of inter-trafficking or cross-talk. In other word, arresting one form of the symptoms leads to elimination of the other. Brain is very susceptible to oxidative stress, sufficient blood flow and constant fresh renewal of cerebrospinal fluid and therefore integrated and concerted approach to the health of brain is important. Once damaged, what is left to our option to cure the disease? My effort and the efforts of scientists as well are occupied with this problem and other related brain disease, and we can develop therapeutics with great confidence. And this website and Viaxon Research Laboratories are all about.