An Integrative View on Intra- and Inter-Cellular Cooperation Mechanisms in Alzheimer’s Disease

Alzheimer’s disease (AD) has been identified as central nervous system pathology more than 100 years ago and for a long time the diagnostic criteria remained the same, based on the anatomopathological findings. Failure of clinical trials in almost every field of AD therapy forced a widening of perspective on molecular pathologies, to the point which, now, AD is considered a multifactorial disease. Recent advancement in AD cell biology uncovered new data regarding amyloid precursor protein and its enzymatic cleavage products, the amyloid beta peptides, such as oligomerization and membrane pore formation. More intracellular deregulated events have been highlighted, e.g. endoplasmic reticulum stress and mitochondrial dysfunction, possibly related through the newly discovered Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM). During the last few years, non-neuronal cell populations came into focus in AD research, such as glial cells, endothelial cells forming the blood-brain barrier or brain non-neuronal stem cells of mesenchymal nature. All these cellular players interact or react to what was considered the central dogma of AD ? the amyloid cascade ? to the point which this dogma is about to be overthrown.