Senile plaque deposition

Alzheimer s disease is characterised neuropathologically by extracellular beta-amyloid (A 3) senile plaque deposition in the grey matter of the brain [123]. Several studies have found saccharides (i.e., GMl ganglioside) on the cell surface. Glycosaminoglycans (GAG) (heparin. 

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)...

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). 

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. 

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. 

The mechanism of AD pathogenesis still remains unclear. However, one mechanism, amyloid (3 (A(3) accumulation, may be due to the disturbance in metal homeostasis in AD brains [Strausak et al., 2001]. A(3 peptides are the major constituents of the amyloid core of senile plaques, which are derived from the amyloid precursor protein (APP) and are secreted into extracelluar spaces. Both APP and A(3 contain a copper-binding domain [Hesse et al., 1994 Atwood et al., 1998]. High concentrations of copper, zinc, and iron have been found within the amyloid deposits in AD brains [Lovell et al., 1998], A(3 peptides can be rapidly precipitated by copper under mildly acidic conditions and by zinc at low physiological (submicromolar) concentrations [Bush et al., 1994], An age-dependent binding between A(3 peptides with excess brain metals (copper, iron, and zinc) induces A(3 peptides to precipitate into metal-enriched plaques [Bush, 2002],... 

It is known that metals such as zinc and copper become more concentrated in the brain with increasing age and that these metals can induce Ab aggregation, thereby enhancing the deposition of senile plaques. In addition, the presence of these metals with Ab initiates the formation of hydrogen peroxide which causes oxidative damage to neurons. By using... 

Q3 Post-mortem examinations of the brains of patients with Alzheimer s disease show loss of cortical neurones and abnormal depositions of proteins in the cerebral tissues. The normal structure of the brain is modified by /l-amyloid plaques, sometimes called senile plaques, and neurofibrillary tangles produced by abnormal neurones. Neurochemical changes in the brain occur, mainly involving cholinergic systems but also other neurotransmitters and neuro modulators. 

Altogether, these studies favor the suggestion that Afl plays a central role in the pathogenesis of AD as a mediator of oxidative stress. Although senile plaques contain deposited Af), the toxic species of Afl is likely small oligomeric species (Drake et al., 2003 Klein et al., 2004 Ashe, 2005 Walsh et al.,... 

Miller, D.L., Papayannopoulos, I.A., Styles, J., Bobin, S.A., Lin, Y.Y., Biemann, K. and Iqbal, K. (1993) Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer s disease. Arch. Biochem. Biophys. 301, 41—52. 

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