A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease

Debomoy Lahiri, Martin Farlow, Kumar Sambamurti, Nigel H. Greig, Ezio Giacobini, Lon S. Schneider

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

Alzheimer's disease (AD), a progressive, degenerative disorder of the brain, is believed to be the most common cause of dementia amongst the elderly. AD is characterized by the presence of amyloid deposits and neurofibrillary tangles in the brain of afflicted individuals. AD is associated with a loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning. AD appears to have a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in one of several genes, such as the β-amyloid precursor protein (APP) and presenilins (PS1, PS2). These proteins along with tau, secretases, such as β-amyloid cleaving enzyme (BACE), and apolipoprotein E play important roles in the pathology of AD. On therapeutic fronts, there is significant research underway in the development of new inhibitors for BACE, PS-1 and γ-secretase as targets for treatment of AD. There is also a remarkable advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. The development of vaccination strategies, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy are examples of new approaches for treating or slowing the progression of AD. In addition, nutritional, genetic and environmental factors highlight more effective preventive strategies for AD. Developments of early diagnostic tools and of quantitative markers are critical to better follow the course of the disease and to evaluate different therapeutic strategies. In this review, we attempt to critically examine recent trends in AD research from molecular, genetic to clinical areas. We discuss various neurobiological mechanisms that provide the basis of new targets for AD drug development. All these current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence.

Original languageEnglish
Pages (from-to)97-112
Number of pages16
JournalCurrent Drug Targets
Volume4
Issue number2
DOIs
StatePublished - Feb 2003

Fingerprint

Alzheimer Disease
Pharmaceutical Preparations
Brain
Amyloid Precursor Protein Secretases
Cholinesterase Inhibitors
Amyloid
Research
Nutrigenomics
Presenilins
Neurofibrillary Tangles
Amyloid beta-Protein Precursor
Cholinesterases
Amyloid Plaques
Brain Diseases
Apolipoproteins E
Pathology
Therapeutics
Oxidants
Cholinergic Agents
Dementia

Keywords

  • Acetylcholine
  • Alzheimer's disease
  • Anticholinesterase
  • APP gene
  • Beta-amyloid
  • Cholinergic agents
  • Cholinesterase
  • Cholinomimetic drugs
  • Dementia
  • NSAID
  • Oxidative stress
  • Phenserine
  • Tau protein

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science

Cite this

A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease. / Lahiri, Debomoy; Farlow, Martin; Sambamurti, Kumar; Greig, Nigel H.; Giacobini, Ezio; Schneider, Lon S.

In: Current Drug Targets, Vol. 4, No. 2, 02.2003, p. 97-112.

Research output: Contribution to journalArticle

Lahiri, Debomoy ; Farlow, Martin ; Sambamurti, Kumar ; Greig, Nigel H. ; Giacobini, Ezio ; Schneider, Lon S. / A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease. In: Current Drug Targets. 2003 ; Vol. 4, No. 2. pp. 97-112.
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