Preclinical and clinical issues in Alzheimer’s disease drug research and development

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Background

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive dysfunction and memory loss, inability to perform the activities of daily living and mood disorders. According to the so-called “amyloid cascade hypothesis”, amyloid-β-peptide (Aβ), produced by beta- and gamma- secretase-mediated cleavages of the amyloid precursor protein (APP), plays a pivotal role in the pathogenesis of AD. Aβ was also shown to contribute to AD pathology by stimulating the hyperphosphorylation of tau thus increasing the formation of neurofibrillary tangles. Recently, the “amyloid cascade hypothesis” was challenged by other theories which lend support to the idea that Aβ is not causative but can be considered as an “innocent bystander” in AD. These hypotheses are based on the evidence that presenilins are involved in the regulation of many pro-survival intracellular pathways including the PI3K/Akt system, the mytogen-activated protein kinases MEK and ERK, the kinase GSK3β, the transcription factor β-catenin and calcium homeostasis. Additionally, presenilin-1 was demonstrated to control the release of N-cadherin, this latter playing a pivotal role in hippocampal long-term potentiation. Therefore, the presenilin-1 mutations found in subjects with familial AD were supposed to interfere with the above mentioned pro-survival pathways thus leading to neurodegeneration.
Although preclinical research generated impressive lines of evidence about the several intracellular mechanism(s) whose impairment lead to the onset and progression of AD, clinical research aimed at the development of new drugs capable of preventing or delaying the onset of neuronal damage in AD patients has produced limited results. The major classes of drugs currently available for the treatment of AD are acetylcholinesterase inhibitors or NMDA glutamate receptor antagonists. The former are used to increase synaptic levels of acetylcholine, which are reduced as a result of damage to cholinergic neurons in the amygdala, hippocampus, and frontal cortex (the brain areas are responsible for the maintenance of memory), whereas the latter are used to prevent/reduce calcium-dependent excitotoxic neuronal cell death. Both classes of drugs have been shown to produce some degree of improvement in the cognitive functions, but their effects are confined largely to patients with mild to moderate AD-like dementia, and the most marked effects are observed during the first year or so of treatment. An alternative to symptomatic treatment with acetylcholinesterase inhibitors involves the use of drugs that intervene in the pathogenesis of the disease, such as γ-secretase inhibitors. These drugs reduce the production of Aβ from the APP, thereby blocking the initial step toward the development of AD. Recently, monoclonal antibodies against Aβ were proposed as novel agents capable to remove Aβ from the brain thus preventing neuronal damage.
The research topic focuses on the preclinical and clinical evidence in support of the different theories about the pathogenesis of AD as well as the potential therapeutic role of new classes of drugs still under preclinical or clinical development.

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