title: Prospects for pharmacological intervention in Alzheimer disease.
abstract: Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of beta-amyloid (Abeta) plaques. Estrogen is believed to have antioxidant or other anti-Abeta effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Abeta deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Abeta drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.
authors.affiliation: Laboratory of Pharmacology, Université Catholique de Louvain Cliniques, Universitaires Saint Luc, Brussels, Belgium. gemilien@aol.com
authors.forename: G
authors.initials: G
authors.lastname: Emilien
authors.forename: K
authors.initials: K
authors.lastname: Beyreuther
authors.forename: C L
authors.initials: CL
authors.lastname: Masters
authors.forename: J M
authors.initials: JM
authors.lastname: Maloteaux
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D000077265:Donepezil; D010450:Endopeptidases / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007189:Indans / Q000627:therapeutic use; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009414:Nerve Growth Factors / Q000494:pharmacology; D009538:Nicotine / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D013619:Tacrine / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D007189:Indans; D009414:Nerve Growth Factors; D010880:Piperidines; D013619:Tacrine; D016202:N-Methylaspartate; D009538:Nicotine; D000077265:Donepezil; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human