On the basis of a recent literature synopsis I suggested that apoptogenic interactions of plasmalemmal type-1 VDAC and Aß peptides induce Alzheimer´s Disease [Letter to the Editor, Mol Gen Metab., 2010, in press, epub ahead].

The proposal may help to connect amyloid Aß peptide shedding of neorons and the increasing neronal loss over the worsening stages of AD.

Human type-1 porin/VDAC (voltage dependent anion channel) shows multi-topological expression. Concerning its function in the plasmalemma the channel is engaged in the regular volume decrease (RVD) of hypotonically stmulated cells or in the apoptotic volume decrease (AVD) of toxically stimulated cells, respectively. It has been demonsrated that the application of several anti-VDAC antibodies on the cell surface of neuronal cells blocks apoptotic reactions, stimulated by staurosporine or amyloid Aß1-42, respectvely. This indicates that opening of plasmalemmal VDAC precedes other established apoptotic steps. However, Aß peptides can be regarded as openers of cell membrane-standing type-1 porin/VDAC channels of neurons, the process ending in the induction of apoptosis. Furthermore, it was recently elaborated that the expression level of the ß-secretase BACE1 increases in deprived hypo-metabolic neuronal cells.

Taken together, a new look at the pathogenesis of Alzheimer´s disease appears: amyloid Aß peptides, cut from APP by ß-secretase BACE1 and g-secretase induce apoptosis by opening type-1 porin/VDAC in the cell membranes of hypo-metabolic neuronal cells, finally ending in Alzheimer´s diease.

Considering the ubiquitous expression modus of APP, ß- and g-secretases and type-1 VDAC/porin a basic model of apoptosis might be given too.