Alzheimer culprits: Cellular crossroads and interplay

Alzheimer's disease (AD) is the primary cause of dementia in the elderly and one of the major health problems worldwide. Since its first description by Alois Alzheimer in 1907, noticeable but insufficient scientific comprehension of this complex pathology has been achieved. All the research that has been pursued takes origin from the identification of the pathological hallmarks in the forms of amyloid-β (Aβ) deposits (plaques), and aggregated hyperphosphorylated tau protein filaments (named neurofibrillary tangles). Since this discovery, many hypotheses have been proposed to explain the origin of the pathology. The “amyloid cascade hypothesis” is the most accredited theory. The mechanism suggested to be one of the initial causes of AD is an imbalance between the production and the clearance of Aβ peptides. Therefore, Amyloid Precursor Protein (APP) synthesis, trafficking and metabolism producing either the toxic Aβ peptide via the amyloidogenic pathway or the sAPPα fragment via the non amyloidogenic pathway have become appealing subjects of study. Being able to reduce the formation of the toxic Aβ peptides is obviously an immediate approach in the trial to prevent AD. The following review summarizes the most relevant discoveries in the field of the last decades.

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► APP processing is dependent on its subcellular localisation and trafficking.
► The interplay between APP and secretase localisation determines Aβ production.
► Numerous interacting proteins tightly regulate APP and secretase trafficking.
► Trafficking default or mutations in APP partners are found in genetic forms of AD.
► Deciphering APP roadmaps and interplay may provide new therapeutic strategies.