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Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs mainly the memory and cognitive function in elderly. Extracellular beta amyloid deposition and intracellular tau hyperphosphorylation are the two pathological events that are thought to cause neuronal dysfunction in AD. Since the detailed mechanisms that underlie the pathogenesis of AD are still not clear, the current treatments are those drugs that can alleviate the symptoms of AD patients. Recent studies have indicated that these symptom-reliving drugs also have the ability of regulating amyloid precursor protein processing and tau phosphorylation. Thus the pharmacological mechanism of these drugs may be too simply-evaluated. This review summarizes the current status of AD therapy.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized clinically by insidious onset of memory and cognition impairment, emergence of psychiatric symptoms and behavioral disorder, and impairment of activities of daily living. It is the most frequent form of dementia found in the elderly. It is estimated that the prevalence of AD over the age of 85 may be as high as 25~50%, and AD is increasingly being recognized as one of the most important medical problems in the elderly. With the increasing number of elderly and growing of life expansion, more people will be suffered from AD, thus give a great economic burden to the families, the care-givers and the whole society. Since detailed molecular mechanisms underline the pathophysiology of AD are still remained to be clarified, currently available drug therapies for AD consist primarily of cholinesterase inhibitors (donepezil, galantamine, rivastigmine, Huperzine A) and an N-methyl-D-aspartate receptor antagonist (memantine) approved by the U.S. Food and Drug Administration (FDA) and some neuroprotective agents. Although these drugs did alleviate some of the psychological and behavioral symptoms of AD patients, effective pharmacological interventions for  treatment of AD, that is, the disease-modifying therapies, are lacking.

During the past decade, many hypotheses have been put forward for AD pathogenesis. Among them, the β-amyloid (Aβ) cascade and the tau hyperphosphorylation are the theories that have widely been accepted. Thus the disease-modifying therapies focus mainly on the agents that will decrease Aβ content and tau hyperphosphorylation.

Cell transplantation and gene therapy for Alzheimer’s disease

The degeneration of the cholinergic neurons in the nucleus basalis of Meynert leads to a reduction in the cholinergic innervation in the cortical and subcortical regions. This reduced neurotransmitter transduction correlates with the clinical and pathological severity of AD and is also a target for treatment. Lack of endogenous nerve growth factor (NGF) can lead to memory deficits, whereas NGF administration rescues neurons from injury-induced cell damage and leads to associated memory improvements and thus NGF is good for gene therapy. In a phase I trial of ex vivo NGF gene delivery in eight individuals with mild AD, fibroblasts genetically modified to express human NGF were transplanted into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. PET studies showed a widespread increase in glucose uptake by cortical neurons after 6~8 months. The cognitive decline is improved as evidenced by the mini-mental status examination (MMSE) and AD Assessment scale. Brain autopsy from one subject suggested robust growth responses to NGF. Although this is a small group and an open-label study with no placebo control, these results are very encouraging.

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