In Alzheimer’s Disease

Calmyrin is closely related to human calcineurin B. Calmyrin interacts with presenilin 2 and may thus be involved in Alzheimer s disease. 

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AA A1 A01.041 Memapsin-1 Candidate beta-secretase in Alzheimer s disease... 

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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)...

Figure 18.5 Schematic representation of possible cleavage sites of APP by a, and y-secretase and the production of j5-amyloid protein. (I) This shows the disposition of APP molecules in 695, 751 and 770 amino-acid chain lengths. Much of it is extracellular. The /1-amyloid (A/I4) sequence is partly extracellular and partly in the membrane. (II) An enlargement of the /1-amyloid sequence. (Ill) Normal cleavage of APP by a-secretase occurs in the centre of A/I4 sequence to release the extracellular APP while the remaining membrane and intracellular chain is broken down by y-secretase to give two short proteins that are quickly broken down. (IV) In Alzheimer s disease ji rather than a-secretase activity splits off the extracellular APP to leave the full AP4 sequence remaining attached to the residual membrane and intracellular chain. 42/43 amino acid )S-amyloid sequence is then split off by y-secretase activity...

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Selkoe, DJ (1999) Translating cell biology into therapeutic advances in Alzheimer s disease. 

Rather scanty evidence exists for the participation of free radicals in Alzheimer s disease and Down s syndrome. However, more recendy, reports have appeared that suggest possible free-radical involvement in the pathogenesis of these two conditions. Zemlan et al. (1989) repotted that the activity of the free-radical scavenging enzyme, SOD, was significantly increased in fibroblast cell lines derived from familial Alzheimer s and Down s patients. They hypothesized that the elevation in SOD activity observed in the Alzheimer patients supports the theory that paired helical filaments are formed by free-radical hydroxylation of proline residues. They further su ested that SOD levels might also be increased in the brains of Alzheimer s and Down s patients, and that the increase in SOD may reflect an enhanced generation of free radicals. 

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