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New players in old amyloid precursor protein‐processing pathways
Author(s) -
Roßner Steffen
Publication year - 2004
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2004.07.004
Subject(s) - amyloid precursor protein , protein kinase c , diacylglycerol kinase , amyloid precursor protein secretase , activator (genetics) , microbiology and biotechnology , senile plaques , chemistry , p3 peptide , biochemistry of alzheimer's disease , biochemistry , signal transduction , biology , alzheimer's disease , receptor , medicine , disease
Abstract The amyloid precursor protein (APP) gives rise to β‐amyloid peptides, which are the main constituents of senile plaques in brains of Alzheimer's disease (AD) patients. The generation of β‐amyloid peptides requires the enzymatic activity of the β‐site APP‐cleaving enzyme 1 (BACE1). BACE1 is primarily expressed by neurons and increased BACE1 protein concentrations and enzymatic activities have been reported in the brains of AD patients. However, there is accumulating evidence that, in addition to neurons, reactive astrocytes are capable of expressing BACE1 and, therefore, may contribute to β‐amyloid plaque formation. This suggests that conditions accompanied by chronic astrocyte activation may contribute to developing AD. Non‐amyloidogenic processing of the APP can be stimulated by phorbol esters (PEs) and by intracellular diacylglycerol (DAG) generation. This led to the hypothesis that classical and novel protein kinase Cs (PKCs), which are activated by DAG/PEs, regulate APP processing. However, in addition to PKCs, there are other DAG/PE receptors present in neurons which may participate in the modulation of APP processing. Munc13‐1, a presynaptic protein with an essential role in synaptic vesicle priming, represents such an alternative target of the DAG second messenger pathway. Using Munc13‐1 knock‐out mice and human neuroblastoma cells transfected with wild‐type and mutant Munc13‐1 constructs it was demonstrated that Munc13‐1 acts independently of and in parallel with PKC to modulate APP metabolism. Therefore, agonists specific for the Munc13‐1 C1‐domain or small molecules mimicking the function of the endogenous Munc13‐1 activator RIM1 may prove useful to shift APP processing towards the non‐amyloidogenic pathway.