User:ThrowTheBar2/Senile Plaque Outline

Senile plaques are visible in light microscopy after staining by silver, Congo red, Thioflavin, cresyl violet, PAS-reaction, and by fluorescence and immunofluorescence microscopy.^[2][4] Bielschowsky silver stain was found to be the least efficient means to visualize senile plaques whereas Campbell silver and Gallyas silver showed approved identification accuracy. Using Congo red only one-fourth of senile plaques present were stained noticeably.^[5] Senile plaques may also be visualized with an immunostain directed against beta amyloid. The primary problem with the above staining methods however is that sections of the neural tissue must be excised from the brain in order to accurately identify senile plaques. This is problematic because removing neural tissue can be as detrimental as the actual plaques themselves.

Concentrated in the synapse of neurons is an Amyloid Precursor Protein (APP) which is a type I integral transmembrane protein. A portion of this protein contains an Aβ peptide sequence. This region comprises part of exon's 16 and 17 of the 18 exon's spanning the gene contained on the Amyloid Precursor Protein.^[6] There are three proteases that can process APP. However, only β- and γ-secretase have been directly implicated in the formation of senile plaques. β-secretase (BACE) analogous to a peptidase enzyme that catabolizes proteins and peptides. This secretase cleaves APP causing the formation of an ammonia, NH2 terminus. A soluble version of APP known as β-APP and a CT99 carboxyl terminal fragment is also produced. After much of APP has been released, γ-secretase proteolysis the remaining carboxyl fragments in the center of the transmembrane domain. The sequential actions of γ-secretase following BACE activity ultimately leads to the formation Aβ.^[6] The pathway leading to the formation of an Aβ fragment is not an unnatural or abnormal occurrence. However, this physiological peptide can collect in the extracellular space. The accumulation of Aβ outside of neuronal synapses that aggregate form a mass known as senile plaques.

Senile plaques can be found in human and animal brains (e.g. mammals and birds). From an age of 60 years (10%) to an age of 80 years (60%) the proportion of people with plaques increases approximately linearly. A small number of plaques can be due to the physiological process of aging. Women are slightly more likely to have plaques than men.^[3] The plaques occur commonly in the amygdaloid nucleus and the sulci of the cortex of brain.

Blocq and Marinesco first described plaques in the grey matter in 1892. Because of their similarity to the actinomyces druses they were called druse necrosis by Oskar Fischer in the beginning of the 20th century. The connection of plaques and demential illness was discovered by Alois Alzheimer in 1906. Bielschowsky supposed in 1911 the amyloid-nature of the plaques. Wisniewski denominated them neuritic plaques in 1973. The second half of the 20th century saw proposed theories of immunological and genetic factors in plaque formation.^[7] Other factors in Alzheimer's disease verification include pathological neurofibrillaries, tangles, and atrophic brain with hydrocephalus. The formation and the distribution of the pathological neurofibrillaries have a regularity^[8] Statistical investigations were performed by J.A.N. Corsellis and M. Franke in the 1970s. M. Franke showed that a demential disease is likely when the number of senile plaques in the frontal cortex is more than 200/mm³. In 1985 succeeded the biochemical identification of beta amyloid. But there are more unsolved questions of formation and importance of the plaque formation.

An important criterion of the neuropathological-histological verification of the Alzheimer’s disease is the formation of senile plaques. Beta amyloid peptide associated with senile plaques has been found to play a central role in the risk, onset, and progression of Alzheimer's disease as well. Of particular importance is the long form of beta amyloid, beta amyloid 42. Elevated beta amyloid levels, as well as elevation of the ratio of beta amyloid 42 to the shorter major form beta amyloid 40, has been identified as important in early events in the pathogenesis of Alzheimer's Disease.^[9] Other factors in Alzheimer's disease verification include pathological neurofibrillaries, tangles, and atrophic brain with hydrocephalus. The formation and the distribution of the pathological neurofibrillaries have a regularity^[8] and allows one to determine the stage of the disease. In combination with the occurrence of a great number of plaques Alzheimer’s disease can be diagnosed with high probability. A correlation between senile plaque presence and Down Syndrome has also been verified.^[1]

An increasing variety of compounds that reduce beta amyloid levels are being identified, several have beta amyloid 42 selectivity whereas others attempt to modulate amyloid precursor protein. Such compounds are now reaching clinical evaluation to determine how they may be of benefit in the treatment of Alzheimer's disease.^[9]

• Proteopathy
• Alzheimer's Disease