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Frontiers in Alzheimer's disease therapeutics.

ABSTRACT: Alzheimer disease (AD) is a progressive neurodegenerative disease which begins with insidious deterioration of higher cognition and progresses to severe dementia. Clinical symptoms typically involve impairment of memory and at least one other cognitive domain. Because of the exponential increase in the incidence of AD with age, the aging population across the world has seen a congruous increase AD, emphasizing the importance of disease altering therapy. Current therapeutics on the market, including cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, provide symptomatic relief but do not alter progression of the disease. Therefore, progress in the areas of prevention and disease modification may be of critical interest. In this review, we summarize novel AD therapeutics that are currently being explored, and also mechanisms of action of specific drugs within the context of current knowledge of AD pathologic pathways.

SUBMITTER: Stone JG

PROVIDER: S-EPMC3129861 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Frontiers in Alzheimer's disease therapeutics.

Stone Jeremy G JG Casadesus Gemma G Gustaw-Rothenberg Kasia K Siedlak Sandra L SL Wang Xinglong X Zhu Xiongwei X Perry George G Castellani Rudy J RJ Smith Mark A MA

Therapeutic advances in chronic disease 20110101 1

Alzheimer disease (AD) is a progressive neurodegenerative disease which begins with insidious deterioration of higher cognition and progresses to severe dementia. Clinical symptoms typically involve impairment of memory and at least one other cognitive domain. Because of the exponential increase in the incidence of AD with age, the aging population across the world has seen a congruous increase AD, emphasizing the importance of disease altering therapy. Current therapeutics on the market, includ ...[more]

PMID: 21743833

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Project description:Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer's disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer's pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer's mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer's, Parkinson's, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer's disease (AD) that have the potential to accelerate therapeutic translation for multiple unmet neurological needs.

Dataset Information

Frontiers in Alzheimer's disease therapeutics.

Publications

Frontiers in Alzheimer's disease therapeutics.

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