Alzheimer’s disease and proteinases

Abstract

Alzheimer’s disease (AD) is the most common form of senile dementia. The disease is characterized by a progressive cognitive decline caused by a loss of neurons from particular regions of the cerebral cortex, accompanied by the presence of amyloid deposition. The core, a central deposit of extracellular amyloid fibrils, is surrounded by dystrophic neurites with activated microglias and reactive astrocytes. Amyloid β protein (Aβ) is a major component of senile plaques and plays a crucial role in the pathogenesis of AD [1–3]. Aβ is a 39–43 amino acid peptide (Fig. 1) produced by abnormal proteolytic processing of the large membrane-bound amyloid precursor protein (APP). Cleavage of APP normally releases a large, soluble N-terminal polypeptide (sAPP). This cleavage occurs within the Aβ region by a putative “α-secretase” (see Fig. 1) and a small 10 kDa C-terminal fragment remains in the membrane. The α-secretory cleavage is known to be due to conventional secretory processing or normal processing and this cleavage precludes further Aβ formation. On the other hand, intact Aβ is produced by abnormal processing that involves the excision of the Aβ region by sequential cutting by putative “β-” and “γ-” secretases. The processing of APP takes place in the trans-Golgi network (TGN) and involves the selective hydrolysis of the substrate from the membrane and the subsequent release of a soluble fragment. Many membrane proteins, such as Fas-ligand, CD43, CD44, L-selectin etc., are now reported to be released from the membrane in this manner. This review will focus on the characteristics of such “secretases” or “sheddases (membrane protein convertases)” involved in the processing of integral membrane proteins, especially APP and presenilins associated with early onset familial AD [4].