Modulation of beta-amyloid production and fibrillization.
Alzheimer's disease (AD) is the most common cause of dementia in old age and presently affects an estimated 4 million people in the U.S.A. and 0.75 million people in the U.K. It is a relentless, degenerative brain disease, characterized by progressive cognitive impairment. In the final stages of the disease, patients are often bedridden, doubly incontinent and unable to speak or to recognize close relatives. Pathological changes of Alzheimer's disease include extensive neuronal loss and the presence of numerous neurofibrillary tangles and senile plaques in the brain. The senile plaques contain amyloid fibrils derived from a 39-43-amino-acid peptide referred to as beta-amyloid or A beta. The basic theory of the so-called 'amyloid hypothesis' is that the deposition of aggregated forms of A beta in the brain parenchyma triggers a pathological cascade of events that leads to neurofibrillary tangle formation, neuronal loss and the associated dementia [1]. Here we discuss progress towards the identification of inhibitors of A beta production and fibrillization.
Allsop
D
D
Department of Biological Sciences, Lancaster University, Lancaster LA1 4YQ, U.K.
Twyman
L J
LJ
Davies
Y
Y
Moore
S
S
York
A
A
Swanson
L
L
Soutar
I
I
D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D005454:Fluorescence Polarization; D006801:Humans; D046911:Macromolecular Substances; D008959:Models, Neurological; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human