[Alzheimer's disease: from brain lesions to new drugs].
We review the main therapeutic targets in Alzheimer's disease. Current treatments include cholinesterase inhibitors and the glutamate-modulating drug memantin. Other neurotransmitters such as serotonin, histamine and noradrenaline may also be targeted. Although useful, however, these symptomatic treatments do not prevent neuronal degeneration and death. Epidemiological studies suggest that treatments given for other reasons, such as antiinflammatory agents (including NSAIDs), cholesterol-lowering drugs, hormone replacement therapy and antioxidants, may prevent or improve Alzheimer-type dementia, but this is not always borne out in controlled clinical trials. Prevention of hypertension significantly reduces the incidence of vascular dementia and of Alzheimer-type dementia, albeit through an unknown mechanism. Alzheimer's disease is characterized by two main lesions: amyloid plaques and neurofibrillary tangles composed of aggregated A Beta peptides and hyperphosphorylated tau. Active and passive immunization against A beta has given promising results. Other exciting approaches include modulation of A beta processing by inhibiting BACE1 or gamma-secretase or upregulating alpha-secretase; A beta peptide catabolism; inhibition of beta fibrillization; and reducing tau phosphorylation or inhibiting tau aggregation. More remote possibilities include gene therapy and the use of growth factors to increase neurogenesis.
Forette
Françoise
F
Université Paris V, Hôpital Broca, Fondation nationale de Gérontologie, International Longevity Center (ILC)-France.
Hauw
Jean-Jacques
JJ
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D023582:Alzheimer Vaccines / Q000627:therapeutic use; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D007167:Immunotherapy; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D033581:Stem Cell Transplantation; D016875:tau Proteins / Q000037:antagonists & inhibitors
D023582:Alzheimer Vaccines; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C054369:MAPT protein, human; D018697:Nootropic Agents; D016875:tau Proteins