Mini-Reviews in Medicinal Chemistry, Volume 2, No. 1, 2002
Alzheimer's
Disease: Targets for Drug Development
Alzheimer’s Disease: Targets For Drug Development Pp. 1-9
A.J. Larner
Cholinergic Drugs in Pharmacotherapy of
Alzheimer's Disease Pp.11-25
P. Camps and D. Muñoz-Torrero
Rational Design of Reversible
Acetylcholinesterase Inhibitors Pp.27-36
X. Barril, S.G. Kalko, M. Orozco, and F. J. Luque
Non-Cholinergic Pharmacotherapy Approaches to
the Future Treatment of Alzheimer's Disease Pp.37-50
Ana Castro, Santiago Conde, M. Isabel Rodriguez-Franco and Ana Martinez
Transgenic Mouse Models with Tau Pathology to
Test Therapeutic Agents for Alzheimer's Disease Pp.51-58
Félix Hernández, Filip Lim, José J. Lucas, Concepción Pérez-Martín,
Franscisco Moreno and Jesús Avila
Pharmacogenomics in Alzheimer's Disease Pp.59-84
Ramón Cacabelos
Towards Alzheimer’s Disease Vaccination Pp.85-92
Beka Solomon
[Back to top] Alzheimer’s Disease: Targets For Drug
Development
A.J. Larner
The numerous advances in the understanding of the
neurobiology of Alzheimer’s disease in the past 15 years have suggested many
new potential targets for therapeutic intervention. This article gives a broad
overview of the spectrum of targets for AD treatment, with particular emphasis
on amyloid b-peptides and tau protein.
[Back
to top] Cholinergic
Drugs in Pharmacotherapy of Alzheimer's Disease
P. Camps and D. Muñoz-Torrero
The cholinergic hypothesis of Alzheimer's disease has spurred the development of numerous structural classes of compounds with different pharmacological profiles aimed at increasing central cholinergic neurotransmission, thus providing a symptomatic treatment for this disease. Indeed, the only drugs currently approved for the treatment of Alzheimer's disease are cholinomimetics with the pharmacological profile of acetylcholinesterase inhibitors. Recent evidence of a potential disease modifying role of acetylcholinesterase inhibitors and M1 muscarinic agonists have led to a revival of this approach, which might be considered as more than a symptomatic treatment.
[Back
to top] Rational
Design of Reversible Acetylcholinesterase Inhibitors
X. Barril, S.G. Kalko, M.
Orozco, and F. J. Luque
A large amount of structural information on AChE and AChE-inhibitor complexes is currently available. Based on that, molecular modeling studies can be intensively used to gain insight into the mechanism of action of the enzyme and the molecular determinants that modulate the potency of inhibitors. In turn, this knowledge can be exploited to design new compounds leading to more effective cholinergic strategies. This manuscript reviews recent developments in the design of reversible acetylcholinesterase inhibitors.
[Back to top] Non-Cholinergic
Pharmacotherapy Approaches to the Future Treatment of Alzheimer's Disease
Ana Castro, Santiago Conde, M. Isabel Rodriguez-Franco and Ana Martinez
Research on the molecular basis of Alzheimer’s disease has elucidated pathogenic pathways from which a range of rational pharmacological interventions has emerged. The most promising strategies involve approaches to retarding, halting or preventing the formation or accumulation of beta amyloid plaques and neurofibrillary tangles. Other therapeutic approaches include those acting via excitatory amino acid receptors, limiting the oxidative stress and inflammatory response associated with dementia, molecules with nerve growth factor like activity. In the present article these and the other recent advances in the neurobiology and pharmacotherapy of AD will be reviewed.
[Back to top] Transgenic Mouse
Models with Tau Pathology to Test Therapeutic Agents for Alzheimer's Disease
Félix Hernández, Filip Lim, José J. Lucas, Concepción Pérez-Martín,
Franscisco Moreno and Jesús Avila
The deposit of two proteins in the brain characterizes
Alzheimer’s disease: deposits of b-amyloid
protein to form senile plaques and tau protein in neurofibrillary tangles. This
review discusses transgenic animals overexpressing normal or mutated tau
protein as well as kinases involved in tau hyperphosphorylation. These animals
hold a great potential as tools to test the effects of forthcoming
therapeutical agents for Alzheimer’s disease.
[Back to top] Pharmacogenomics in Alzheimer's Disease
Ramón Cacabelos
Alzheimer's disease (AD) is a complex disorder associated with multiple genetic defects either mutational or of susceptibility. Information available on AD genetics does not explain in full the etiopathogenesis of AD, suggesting that environmental factors and/or epigenetic phenomena may also contribute to AD pathology and phenotypic expression of dementia. The genomics of AD is still in its infancy, but is helping to understand novel aspects of the disease including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically-regulated metabolic cascades. AD genomics is also helping to develop new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerate drug development for AD and other complex disorders.
Main genes involved in AD include mutational loci (APP, PS1, PS2, TAU) and multiple susceptibility loci (APOE, A2M, AACT, LRP1, IL1A, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3B, NOS) distributed across the human genome. Genomic associations integrate bigenic, trigenic, tetragenic or polygenic matrix models to investigate the genomic organization of AD in comparison to the control population. Similar genetic models are used in pharmacogenomics to elucidate genotype-specific responses of AD patients to a particular drug or combination of drugs. Using APOE-related monogenic models it has been demonstrated that the therapeutic response to drugs in AD is genotype-specific. A multifactorial therapy combining 3 different drugs yielded positive results during the 6-12 months in approximately 60% of the patients. With this therapeutic strategy, APOE-4/4 carriers were the worst responders, and patients with the APOE-3/4 genotype were the best responders. In bigenic and trigenic models it was possible to differentiate the influencial effect of PS1 and PS2 polymorphic variants on mental performance in response to multifactorial therapy.
The application of functional genomics to AD can be a suitable strategy for harmonization in molecular diagnosis and drug clinical trials. Furthermore, the pharmacogenomics of AD may contribute in the future to optimise drug development and therapeutics, increasing efficacy and safety, and reducing side-effects and unnecessary costs.
[Back to top] Towards Alzheimer’s
Disease Vaccination
Beka Solomon
Active and passive immunization against fibrillar b-amyloid of various mice models of
Alzheimer’s disease leads to the disaggregation and inhibition of plaque
formation. Preliminary results showing improved behaviour and memory function
obtained after administration of anti-b-amyloid
vaccines to transgenic mice encourage these and related approaches for testing
in the treatment and prevention of Alzheimer’s disease.