Emerging beta-amyloid therapies for the treatment of Alzheimer's disease.
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular neuritic plaques comprised of fibrillar deposits of beta-amyloid peptide (Abeta) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase inhibitors, treat the symptoms but do not modify the progression of the disease. The etiology of AD is unclear. However, data from familial AD mutations (FAD) strongly support the "amyloid cascade hypothesis" of AD, i.e. that neurodegeneration in AD is initiated by the formation of neurotoxic beta-amyloid (Abeta) aggregates; all FAD mutations increase levels of Abeta peptide or density of Abeta deposits. The likely link between Abeta aggregation and AD pathology emphasizes the need for a better understanding of the mechanisms of Abeta production. This review summarizes current therapeutic strategies directed at lowering Abeta levels and decreasing levels of toxic Abeta aggregates through (1) inhibition of the processing of amyloid precursor protein (APP) to Abeta peptide, (2) inhibition, reversal or clearance of Abeta aggregation, (3) cholesterol reduction and (4) Abeta immunization.
Conway
Kelly A
KA
Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA 19477, USA. kconway3@prdus.jnj.com
Baxter
Ellen W
EW
Felsenstein
Kevin M
KM
Reitz
Allen B
AB
D000544:Alzheimer Disease / Q000378:metabolism* / Q000628:therapy*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D002784:Cholesterol / Q000378:metabolism; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D016233:Immunotherapy, Active; D051379:Mice; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000900:Anti-Bacterial Agents; D001057:Apolipoproteins E; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse