Current Alzheimer Research - Volume 7, Issue 3, 2010

Alzheimer's disease (AD) drug discovery researchers face immense challenges in developing drugs that get into the brain, are safe and ultimately produce clinically meaningful results. Perhaps even more challenging is determining at what point in the disease cascade is best to intervene. We know that many different pathways initiate or exacerbate disease progression [1]. Amyloid-β (Aβ), the main component of amyloid plaq Read More

Memory loss is a prominent health concern, second only to heart disease for older individuals. Docosahexaenoic acid (DHA), the principle omega-3 fatty acid in brain and heart, plays an important role in neural and cardiac function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly and Alzheimer's patients. Higher DHA intake and plasma levels are inversely correlated with increased relative risk of Read More

Risk for Alzheimer's disease escalates dramatically with increasing age in the later decades of life. It is widely recognized that a preclinical condition in which memory loss is greater than would be expected for a person's age, referred to as amnestic mild cognitive impairment, may offer the best opportunity for intervention to treat symptoms and modify disease progression. Here we discuss a basis for age-related memory impair Read More

As the mechanisms underlying neuronal development and degeneration become clarified, a number of common effectors and signaling pathways are becoming apparent. Here we describe the identification of Aβ, long considered a pathologic mediator of Alzheimers Disease and Down Syndrome, as similarly over-expressed in the neurodevelopmental disease, Fragile X Syndrome. We also show that mGluR5 inhibitors, cu Read More

Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Aβ from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting γ-secretase, which generates the C-terminus of Aβ; however, γ- secretase inhibitors cause serious toxicities due to interference with the N Read More

Despite the long history of drug discovery from natural sources, the marine environment, which covers 70% of the Earth's surface, is still relatively unexplored. Intense competition for limited resources drives the evolution of specific and potent chemical defenses distinct from their terrestrial counterparts. Based on this rationale, we recently began screening extracts derived from marine invertebrate and cyanobacterial sampl Read More

Accumulation and deposition of beta amyloid (Aβ) play a critical role in the pathogenesis of Alzheimer's Disease (AD), and numerous approaches to control Aβ aggregation are being actively pursued. Brain Aβ levels are controlled by the action of several proteolytic enzymes such as neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin. While up-regulation of these enzymes increased clearance of Aβ in transgenic mous Read More

The accumulation of the amyloid-beta peptide (Aβ) continues to emerge as a central factor in Alzheimer's disease (AD). In recent years attention has been drawn to clearance mechanisms of Aβ as evidence suggests reduced clearance may be linked to late-onset AD. Direct degradation of Aβ by endopeptidases has emerged as one critical pathway of clearance. Of particular interest are endopeptidases that are sensitive to the Read More

Alzheimer's disease is diagnosed by postmortem detection of pathological lesions that accumulate in specific brain regions. Although the presence of both β-amyloid plaques and tau-bearing neurofibrillary lesions defines Alzheimer's disease, the distribution of neurofibrillary lesions alone correlates strongly with neurodegeneration and cognitive decline. A whole-brain imaging test capable of detecting these lesions in prem Read More

Tau aggregation is an appealing target for therapeutic intervention. However, conformational change or aggregation needs to be targeted without inhibiting the normal biology of tau and its role in microtubule stabilization. The number of compound classes being tested at this time are very limited and include Congo red derivatives [1], anthraquinones (Pickhardt et al. 2005 [2], disputed in Crowe et al. 2007 [3]), 2,3-di(furan-2 Read More

Dephosphorylation (activation) of cofilin, an actin binding protein, is stimulated by initiators of neuronal dysfunction and degeneration including oxidative stress, excitotoxic glutamate, ischemia, and soluble forms of β-amyloid peptide (Aβ). Hyperactive cofilin forms rod-shaped cofilin-saturated actin filament bundles (rods). Other proteins are recruited to rods but are not necessary for rod formation. Neuronal cytoplas Read More

Positron emission tomography (PET) imaging of Alzheimer's Disease (AD) offers the potential to provide early onset diagnosis and subsequent intervention, including guided treatment regimens. One of the restricting factors in clinical application of PET technology is the limited availability of radioligands with affinity to specific targets of interest. Given the short half-life of the most popular positron emitter currently used (18F; Read More

Cannabinoids have been shown to increase neurogenesis in adult brain, as well as protect neurons from excitotoxicity, calcium influx, inflammation, and ischemia. Recent studies have shown that synthetic cannabinoids can alleviate water maze impairments in rats treated with intracranial amyloid β protein (Aβ); however it is unknown whether this effect is due to the cannabinoids' anti-inflammatory properties or whether it Read More

High levels of cholesterol have been proposed as a risk factor for Alzheimer's disease (AD). Polymorphism of genes encoding proteins that regulate cholesterol metabolism have also been associated with the frequency of Alzheimer's development. Some studies have shown that cholesterol-lowering drugs reduce the frequency of AD development. The proposed role of cholesterol in AD has been challenged by several studies Read More

The MCI construct aims to investigate the grey area existing between normal aging and dementia, in order to identify in the preclinical stage patients at risk of developing dementia. The construct of the MCI has been proposed by taking the neuropathological staging of the Alzheimer's disease (AD) as reference and providing an explicit set of identifying criteria, but it has raised two main problems: (a) the variability of es Read More