β-Amyloid therapies in Alzheimer’s disease

Abstract

Neurones in the brain produce beta-amyloid fragments from a larger precursor molecule termed the amyloid precursor protein (APP). When released from the cell, these protein fragments may accumulate in extracellular amyloid plaques and consequently hasten the onset and progression of Alzheimer's disease (AD). A beta fragments are generated through the action of specific proteases within the cell. Two of these enzymes, beta- and gamma-secretase, are particularly important in the formation of A beta as they cleave within the APP protein to give rise to the N-terminal and C-terminal ends of the A beta fragment, respectively. Consequently, many researchers are investigating therapeutic approaches that inhibit either beta- or gamma-secretase activity, with the ultimate goal of limiting A beta; production. An alternative AD therapeutic approach that is being investigated is to employ anti-A beta antibodies to dissolve plaques that have already formed. Both of these approaches focus on the possibility that accrual of A beta leads to neuronal degeneration and cognitive impairment characterised by AD and test the hypothesis that limiting A beta deposition in neuritic plaques may be an effective treatment for AD.

Disassembly of Amyloid Fibrils by Premicellar and Micellar Aggregates of a Tetrameric Cationic Surfactant in Aqueous Solution

“…In 1991, Hardy et al proposed that β-amyloid (Aβ) deposits were the fundamental cause of AD. Mechanisms aimed at preventing or reversing accumulation of amyloid deposits are being actively pursued, and knowledge of the details of Aβ metabolism and plaque formation, hyperphosphorylation of tau, and the formation of tangles is constantly expanding. Lines of research of disease-modifying drug therapies including Aβ clearance from the brain and the inhibition of Aβ production and aggregation into plaques are underway .…”

Managing Alzheimer Dementia Tomorrow

“…8 ␤-Amyloid is generated from large structural molecules called amyloid precursor proteins. 9 Amyloid precursor proteins are transmembrane glycoproteins that play a role in cellular adhesion and membrane integrity. They are found in intracellular vesicles, such as the endoplasmic reticulum, Golgi apparatus, endosomes, and neurotransmitter secretory tubules, as well as the cell wall.…”

“…9 There are also several cofactors necessary to activate secretase that may be manipulated to decrease the formation of ␤-amyloid. These include the cell surface immunoglobulin molecule receptor for glycation end products (RAGE) and ␤-amyloid binding alcohol dehydrogenase (ABAD).…”

Design and Synthesis of Highly Potent Benzodiazepine γ-Secretase Inhibitors: Preparation of (2S,3R)-3-(3,4- Difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]- diazepin-3-yl)butyramide by Use of an Asymmetric Ireland−Claisen Rearrangement

“…Introduction. The 40−42 amino acid amyloid-β (Aβ) peptide is the major component of the extracellular proteinaceous plaques seen in Alzheimer's disease (AD), and much evidence suggests a pivotal role for Aβ in the disease process. , In particular, individuals possessing autosomal dominant mutations in the genes encoding for amyloid-β precursor protein (βAPP) or the membrane-bound protein homologues presenilin 1 and 2 have elevated Aβ levels and suffer from aggressive forms of early onset AD. − These observations have led to the hypothesis that Aβ, in its soluble form or when aggregated into oligomers, fibrils, and subsequently plaques, is responsible for neuronal toxicity and cell death …”

“…Results and Discussion. Previous work within our group had identified 1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e] [1,4]diazepines bearing an N-hydrocinnamide side chain at the 3-position to be a novel class of γ-secretase inhibitors. 21 Introduction of a substituent at the R-position of the side chain as in 1 (320 nM) or 2 (15 nM) was found to greatly increase potency.…”