Plaques, senile

Amyloid precursor protein (APP) is the precursor of (3-amyloid, the main component of senile plaques found in the brain of Alzheimer patients. The production of (3-amyloid from APP to the cells from abnormal proteolytic cleavage of the amyloid precursor protein. Enzymes involved in this cleavage may be suitable targets for the therapy of Alzheimer s disease. 

Despite its characteristic symptoms and even after the exclusion of other established causes, AzD can only be reliably diagnosed by neuropathology and microscopic examination of the brain. Indeed that is how it came by its name. In 1907, a German physician, Alois Alzheimer, described two distinct post-mortem changes in the brain of a woman patient who had died with an unusual mental illness. These were the now characteristically accepted markers of the disease, namely senile plaques and neurofibrillary tangles (Fig. 18.1). 

Most cases of AzD show cerebrovascular amyloid deposits and the amyloid protein of senile plaques is the same as that found in blood vessels. It is referred to as )S-amyloid protein and is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP, which is a transmembrane protein and although its precise function is not clear, it is widely distributed and APP knock-out mice show reduced motor function. Normally so-called short 40 amino-acid-soluble derivatives of APP are produced by proteolytic cleavage of APP within the j] (A4) amino-acid sequence but APP can also be cleaved... 

Figure 18.2 Production of senile plaque (S/A4 amyloid protein. Amyloid fS4 protein (/S/A4) is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP. This is a transmembrane protein which is normally cleared within the fi/A4 amino acid sequence to give short 40 amino-acid soluble derivatives. It seems that under some circumstances as in Alzheimer s disease, APP is cleared either side of the fi/A4 sequence to release the 42/43 amino acid P/A4 which aggregates into the amyloid fibrils of a senile plaque (a). (See also Fig. 18.5.) Some factors, e.g. gene mutation, must stimulate this abnormal clearage leading to the deposition of P/A4 amyloid protein as plaques and tangles and the death of neurons (b)...

Perry, EK, Tomlinson, BE, Blessed, G, Bergmann, K, Gibson, PH and Perry, RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Brit. Med. J. 2 1457-1459. 

The identification, using analytical microprobe and solid-state magic-angle nuclear magnetic resonance (NM techniques, of aluminosilicate deposits in the cores of the pathognomic senile plaques in the brains of Alzheimer subjects (Candy et al., 1986) has prompted widespread scientific and public concern, and controversy with regard to the possible aetiological role of environmental aluminium and aluminosilicates in senile dementia (Walton, 1991). 

Evidence for a neuroimmunological involvement in Alzheimer s disease is accumulating. Activation of the complement cascade by beta amyloid (Rogers et al., 1992), the recruitment, proliferation and activation of microglia in intimate juxtaposition to the senile plaques (Davis et al., 1992), and the increased synthesis of microglia-derived pro-inflammatory cytokine interleukin-1 (Griffin et al., 1989) is indicative of a chronic inflam-... 

Namba, Y., Kawatsu, K., Izumi, S., Ueki, A. and Ikeda, K. (1992). Neurofibrillary tangles and senile plaques in brain of elderly leprosy patients. Lancet 340, 978. 

Rees, S. and Cragg, B. (1983). Is silica involved in neuritic (senile) plaque formation Acta Neuropath. 59, 31-40. 

Kitt, C.A. Walker, L.C. Molliver. M.E. and Price, D.L. Serotoninergic neurites in senile plaques in cingulate cortex of aged nonhuman primate. Synapse 3 12-18, 1989. 

Pathologic hallmarks of the disease in the brain include neurofibrillary tangles and neuritic plaques (senile plaques)... 

Neuritic or senile plaques are extracellular protein deposits of fibrils and amorphous aggregates of P-amyloid protein.11 This formed protein is central to the pathogenesis of AD. The P-amyloid protein is present in a non-toxic, soluble form in human brains. In AD, conformational changes occur that render it insoluble and cause it to deposit into amorphous diffuse plaques associated with dystrophic neuritis.14 Over time, these deposits become compacted into plaques and the P-amyloid protein becomes fibrillar and neurotoxic. Inflammation occurs secondary to clusters of astrocytes and microglia surrounding these plaques. 

Neuritic (senile) plaques Microscopic lesions composed of fragmented axon terminals and dendrites surrounding a core of amyloid seen in the cerebral cortex in Alzheimer s disease. 

Alzheimer s disease Neocortex, hippocampus (J Peptide 4R, 3R tau Diffuse and senile plaques,... 

Amyloid protein A 42-amino acid protein found in the core of the microscopic senile plaques in the brains of individuals with Alzheimer s disease, p-amyloid protein is synthesised from the much larger amyloid precursor protein (APP). 

Iwatsubo, T., Odaka, A., Suzuki, N. et al. Visualization of A[3 4243 and A[3 40 in senile plaques with end-specific A[3 mono-clonals evidence that an initially deposited species is A[3 4243. Neuron 13 45-53,1994. 

Figure 17.5. The precursor molecule APP and the three different proteases a, (i, y secretase that are involved in the processing of APPto fS-amyloid peptide. The aberrant processing of the amyloid precursor protein (APP) leads to accumulation of beta-amyloid fragments, first as protofibrils and then as fibers that aggregate in the senile plaque structures. (See color insert.)...

In general, heterogeneities in structural materials are often the source of mechanical failure, but specific types also provide ways to disperse energy without failure. For example, some silks, at a microscopic and macroscopic level, are able to form structures such as spherulite inclusions that will develop into elongated cavities in the solid fibers (Akai, 1998 Frische et al., 1998 Robson, 1999 Tanaka et al., 2001). Interestingly, Isobe et al. (2000), in a significant but largely overlooked paper, showed that synthetic A/ i 4o produced spherulites that had the essential features of Alzheimer s amyloid senile plaques (Kaminsky et al., 2006). 

Isobe, I., Yanagisawa, K., and Michikawa, M. (2000). A possible model of senile plaques using synthetic amyloid /(—protein and rat glial culture. Exp. Neurol. 162, 51-60. 

APP is endoproteolytically processed by BACEl and y-secretase to release ABPl-40 and ABPl-42, which aggregate to form senile plaques in AD brains. The C-terminus of ABP, C99, is generated by y-secretase, which has activity that is dependent on PSl or PS2. It has been suggested that PS proteins are the catalytic core of the proteolytic activity of the complex, but a number of other proteins mandatory for y-secretase cleavage have also been discovered. The exact role of PS in the y-secretase activity remains a matter of debate because cells devoid of PS still produce some forms of ABP. 

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