Current and future implications of basic and translational research on amyloid-ß peptide production and removal pathways.

Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid ß-peptide (Aß). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aß produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aß. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aß. We also briefly outline how the emerging knowledge about the pathways involved in Aß generation and clearance can be potentially targeted therapeutically. This article is part of Special Issue entitled "Neuronal Protein".

Galantamine-based hybrid molecules with acetylcholinesterase, butyrylcholinesterase and γ-secretase inhibition activities.

We previously designed novel peptides-containing galantamine analogues. These compounds we analyzed for their putative inhibitory effect towards acetylcholinesterase, butyrylcholinesterase and γ-secretase, three activities of which could be central to various neurodegenerative pathologies including Alzheimer's disease. These pharmacological agents were virtually equipotent on acetylcholinesterase activity but display drastically higher inhibitory activities towards butyrylcholinesterase with several compounds displaying an about 100-fold higher activity than that harboured by galantamine. Strikingly, two of the galantamine amides that displayed low activity towards acetylcholinesterase exhibited the highest inhibitory potency towards butyrylcholinesterase (106 to 133 times more active than galantamine). Interestingly, five compounds show a rather good γ-secretase inhibitory potency while they retain their ability to inhibit AChE and/or BuChE activity. Thus, we have been able to design novel compounds with significant inhibitory activity against several of the enzymes responsible for key dysfunctions taking place in several neurodegenerative diseases. These mixed inhibitors could therefore be envisioned as potential pharmacological tools aimed at circumventing the degenerative processes taking place in these major pathologies.