A number of groups are developing nicotinic α-7 receptor agonists or partial agonists for the treatment of Alzheimer’s disease. It is believed that α-7 agonists may contribute to symptomatic treatment through cholinergic mechanisms and may also protect vulnerable neurons from the neurotoxic effects of β-amyloid peptides. Although α-7 agonists have shown positive effects on cognition in both animal models and Alzheimer’s disease patients, researchers at the Salk Institute have suggested that ‘Nicotinic Receptor May Help Trigger Alzheimer’s Disease’, and propose that nicotinic α-7 receptor antagonists may be a better target for the treatment of Alzheimer’s disease.

The team found that, whereas transgenic mice that overexpress a mutated form of human amyloid precursor protein (APP) perform poorly in learning and memory tests, mice that overexpress APP but also lack nicotinic α-7 receptors perform as well as wild type mice. β-Amyloid disrupts the function of nicotinic α-7 receptors and is believed to accumulate in neurons via high affinity binding to the receptors. Agonist stimulation of α-7 receptors could thus restore impaired or altered intracellular signalling caused by β-amyloid and, by desensitisation or competitive binding, could also prevent internalisation of β-amyloid. Although it is likely that α-7 receptor antagonists would also prevent internalisation of β-amyloid, there is currently little other information to support the development of antagonists, especially given the toxicities of known α-7 receptor antagonists such as α-bungarotoxin and methyllycaconitine.

The study is published in the Journal of Neuroscience.

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Although not without opponents – and still unproven – the theory that reducing levels of β-amyloid peptides will lessen neuronal damage and cognitive deficits remains a central tenet of Alzheimer’s disease research and the focus of many pharmaceutical companies. Last week, however, it was reported at the Alzheimer’s Association annual meeting in Vienna that Dimebon^® (latrepirdine), a drug which has shown clinical benefit in people with mild to moderate Alzheimer’s disease, increases levels of β-amyloid in the releasate from isolated nerve terminals and in the interstitial fluid from the brains of transgenic mice bred to model Alzheimer’s disease. This unexpected result raises questions about how Dimebon^® works and also, perhaps, about the validity of the ‘amyloid hypothesis’. One possibility is that the neuroprotective effects of Dimebon^® are sufficient to outweigh the adverse effects of increased concentrations of β-amyloid. Preclinical studies have suggested that Dimebon^® could prevent neuronal damage and dysfunction by stabilising or improving mitochondrial function. In addition, biochemical studies have shown effects on α-adrenergic receptors, histamine receptors and serotonin receptors as well as on Ca²⁺ flux and apoptosis. Alternatively, Dimebon^® could cause an acute increase in amyloid levels, but lower levels on chronic dosing, or it could play a role in amyloid transport. Whatever the explanation for the present results, further investigations into the mechanism of action of Dimebon® and the relevance of animal models of acute amyloid lowering to human disease are of key importance.

Dimebon^®, which has been used in Russia to treat hayfever since the 1980s, is being jointly developed by Medivation and Pfizer and is currently in phase III clinical trials.

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The complement system is a complex cascade of reactions forming a central component of the innate immune system which assists in the removal of invading pathogens and cellular debris, and in the processing of immune complexes. There is substantial evidence that complement activation is associated with amyloid plaques in the brains of Alzheimer’s disease patients, although whether this is beneficial or detrimental has been unclear.

Writing in the Journal of Immunology, US and Australian scientists have now described the effect of administration of an antagonist of the receptor for the complement activation product, C5a, in animal models of Alzheimer’s disease. Oral administration of PMX205 in drinking water for 2-3 months resulted in substantial reductions in disease markers such as fibrillar amyloid deposits and activated glia in two mouse models of Alzheimer’s disease. The reduction in pathological markers correlated with improved performance in a passive avoidance task in Tg2576 mice. In 3xTg mice, PMX205 also significantly reduced hyperphosphorylated tau.

PMX205 is a cyclic hexapeptide derivative that was developed by Promics as a second generation C5a receptor antagonist for the treatment of inflammatory disorders, including inflammatory bowel disease. An earlier compound, PMX53, was found to be well tolerated in phase I clinical trials for rheumatoid arthritis and psoriasis.

The new study shows for the first time that antagonists of the C5a receptor interfere with inflammation and neurodegeneration in mouse models of Alzheimer’s disease and could, one day, lead to new treatments for human patients.

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Histones are basic proteins that interact with negatively charged phosphate groups on DNA, compacting and protecting the DNA, and controlling gene expression. Histones are subject to a number of post-translational modifications, including methylation and acetylation. The balance between acetylation by histone acetyltransferases (HAT) and deacylation by histone deacetylases (HDAC) alters the strength of DNA interactions and plays a key role in regulating gene expression.

Collaborators led by scientists at the Picower Institute for Learning and Memory have identified a promising target that could enable the development of therapeutics to improve memory and learning in patients with neurodegenerative disorders such as Alzheimer’s. The team demonstrated that treatment with HDAC inhibitors enhanced memory and learning ability in normal mice and mouse models of neurodegeneration.

Histone and DNA are the major components of chromatin, the complex that packages genetic information into the chromosomes and inhibitors of the HDAC family have received much attention in recent years as potential treatments for various cancers. Chromatin modification, particularly via deacetylation, has also been implicated in memory formation.

Although HDACs are a family of 11 members, the team has shown that neuron-specific overexpression of HDAC2, but not HDAC1, in mice decreased synaptic plasticity, synapse number and memory formation. This effect was ameliorated by treatment with HDAC inhibitors. Conversely, Hdac2 deficient mice displayed enhancement of synapse number and memory facilitation.

The results, published in full in the journal Nature, suggest exploration of selective HDAC2 inhibitors for treatment of human neurodegenerative diseases involving memory impairment.

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Although definitive proof of a causative link between aggregation of amyloid peptides (Aβ) and Alzheimer’s disease (AD) remains elusive, much effort has been devoted to devising means of lowering Aβ levels. The ability to assess the effectiveness of such therapies in the clinic has so far been hampered by the lack of a method to determine drug effects on Aβ production or clearance from the human CNS. Aβ is produced by the action of β- and γ-secretases on amyloid precursor protein (APP) and is degraded by a number of enzymes, including insulin-degrading enzyme (IDE) and neprilysin. Inhibitors of both β- and γ-secretase have been developed as potentially disease-modifying treatments, although it is unclear whether increased production, reduced clearance, or a combination of both is responsible for elevated levels of Aβ ?in AD patients. Writing in the Annals of Neurology, researchers at Washington University School of Medicine have now described the use of a recently developed technique known as stable isotope-linked kinetics (SILK) to determine the effect of a γ-secretase inhibitor, LY450139 (semagacestat), on production of Aβ. In a double-blind study, 20 healthy volunteers were assigned to receive varying doses of LY450139 or placebo (n = 5 per group). The volunteers also received an intravenous infusion of a labelled form of the amino acid leucine which, over the course of a couple of hours, became incorporated into newly synthesised proteins, including Aβ. By periodically sampling cerebrospinal fluid (CSF), the team were able to monitor the proportion of labelled Aβ to give a measure of the rate of production. CSF sampling was continued after the labelled leucine infusion was switched off to provide a measure of the rate of Aβ clearance. The results suggested that LY450139 caused a dose-dependent decrease in Aβ production, with an 84% reduction at the highest dose (280mg). There were no differences in Aβ clearance between the placebo and drug treated groups. The SILK procedure takes 36 hours but offers the potential for clearer interpretation of drug effects since analysis of measurements of unlabelled Aβ in CSF is confounded by natural fluctuations in levels.

Ongoing clinical studies are looking at the effect of LY450139 on cognitive function and biochemical and brain imaging biomarkers in AD patients.

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There is no single test that will diagnose Alzheimer’s disease (AD) and a diagnosis of possible or probable AD is currently based on neuropsychological tests together with advanced brain imaging techniques such as functional MRI or PET scans. Simple and reliable diagnostic tests for AD are much needed, and researchers at the University of Georgia have now shown that the levels of two antibodies in the blood correlate with the severity of AD symptoms and may provide just such a test. The team had previously shown that levels of anti-Aβ and anti-RAGE antibodies were significantly higher in AD patients than in healthy individuals and the latest study reveals a direct relationship between the severity of disease and the levels of the two antibodies. Much evidence points to a link between AD and elevated levels of β-amyloid (Aβ) peptides. Binding of Aβ to neuronal membrane receptors for advanced glycation end products (RAGE) is believed to trigger inflammation and contribute to the neurological damage characteristic of AD.

Although it could be years before a diagnostic test based on their work is available for clinical use, the researchers hope that it will, one day, provide a way of identifying people with early AD and those at risk of developing the disease. The study is published in full in The Journals of Gerontology.

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Mis-folded prion proteins have been linked to a number of neurological diseases including scrapie in sheep, bovine spongiform encephalopathy (BSE, “mad cow disease”) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. A new study by researchers at Yale University now suggests a link between normal prion proteins and Alzheimer’s disease. The accumulation of insoluble amyloid plaques in the brain is a hallmark of Alzheimer’s disease. Soluble β-amyloid oligomers also accumulate in the brain and cause damage to neurons and synapses, although precisely how this happens is not clear. Using gene expression analysis, the Yale team identified normal, correctly folded, cellular prion protein (PrP^c) as a cell surface receptor for oligomeric β-amyloid. PrP^c binds β-amyloid oligomers with nanomolar affinity and the interaction does not require the infectious PrP^Sc conformation of prion protein that is linked to scrapie, BSE and CJD. Binding of β-amyloid was associated with a specific region on the prion protein and could be blocked by an antibody directed against this site. The team found two other receptors that also bind β-amyloid, but with weaker affinity than PrP^c. β-Amyloid oligomers are known to interfere with long term potentiation (LTP), a process that may be linked to learning and memory. In brains from mice lacking PrP^c, LTP was not affected by the presence of β-amyloid, suggesting that blocking the interaction between β-amyloid and PrP^c may be a new way to treat Alzheimer’s disease. The normal function of PrP^c is still under investigation.

The study is published in the February 26^th issue of the journal Nature.

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Cleavage of amyloid precursor protein (APP) by β- and γ-secretases into neurotoxic β-amyloid peptides is believed to play a leading role in the development of Alzheimer’s disease, although clinical proof of this hypothesis remains elusive. Researchers at Genentech and the Salk Institute have now discovered a new pathway by which APP could contribute to the development of Alzheimer’s disease. The researchers propose that interaction of an N-terminal extracellular domain of APP (N-APP) with death receptor 6 (DR6) triggers widespread caspase-mediated neuronal destruction and axonal pruning. DR6 is expressed by developing neurons and, together with APP, plays a key role in remodelling the embryonic brain during development by triggering apoptosis in neurons and pruning axons that fail to make productive connections. Axonal pruning was found to require caspase 6 whereas cell body apoptosis requires caspase 3.

Although the team has yet to demonstrate that N-APP causes Alzheimer’s disease and the mechanism underlying reactivation of the pruning process in adults is, as yet, unknown, the discovery identifies several new potential targets for the treatment of Alzheimer’s disease. The study does not rule out a role for β-amyloid peptides in the pathogenesis of Alzheimer’s disease but suggests that blocking the action of N-APP on DR6, either directly or via downstream pathways, may also provide benefit.

The study is published in the February 19^th advanced online issue of the journal Nature.

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Available treatments for Alzheimer’s disease offer relatively small symptomatic benefits and more effective treatments are much needed. β-Amyloid has been implicated in the pathogenesis of Alzheimer’s disease and much attention has focussed on inhibiting two enzymes responsible for production of this peptide, the β- and γ-secretases. Although potent inhibitors of both enzymes have been identified, achieving robust activity in animal models and progression to clinical studies has proved more challenging. Using a high-throughput functional genomics screen, scientists at VIB and Galapagos Pharmaceuticals have now identified a constitutively expressed orphan G protein-coupled receptor, GPR3, as another modulator of β-amyloid production. GPR3 is highly expressed in areas of the brain associated with Alzheimer’s disease and levels are elevated in brain tissue from people with sporadic Alzheimer’s disease. The researchers showed that blocking GPR3 prevented accumulation of β-amyloid, both in cell culture experiments and in a mouse model of Alzheimer’s disease.

Since G protein-coupled receptors have been relatively easy to exploit as drug targets, the scientists hope that GPR3 will prove to be a promising target for the treatment of Alzheimer’s disease.

The study is published in the February 13^th issue of the journal Science.

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There are no medicines that can prevent Alzheimer’s disease and current drugs ease symptoms but do little to stop progression of the disease. There is consequently much current interest in whether lifestyle choices or herbal remedies can prevent or alter the course of Alzheimer’s disease. Two recent reports describe the effect of marijuana-like compounds in elderly rats and extracts of Gingko Biloba in elderly humans.

Previous work has suggested that people who regularly smoked marijuana in the 1960s and 1970s are less likely to develop Alzheimer’s disease in later life. Now scientists at Ohio State University have described details of how constituents of marijuana can combat inflammation and possibly stimulate neurogenesis. The team had found that treatment with WIN-55212-2, a compound with similar pharmacological properties to tetrahydrocannabinol (THC), made a small improvement to the ability of elderly rats to perform memory tests. They then went on to look at how the drug was working, and showed that it lowered inflammation in the hippocampus by acting on the TRPV1 receptor. The team also showed that the action of WIN-55212-2 on CB₁ and CB₂ receptors led to the generation of new brain cells. The group are continuing to investigate which receptors are most important for reducing inflammation and stimulating neurogenesis. This knowledge could lead to the discovery of new drugs to reduce inflammation and increase the production of new neurons before memory loss becomes apparent.

WIN55212-2 is a full agonist at the CB₁ receptor and is not approved as a drug since it elicits cannabis-like effects in humans.

A second report discusses the results of the first randomized, double-blind trial to assess the effectiveness of Ginkgo biloba in reducing the incidence of dementia. Ginkgo is an antioxidant that helps to protect cells in vitro from oxidative damage. Some studies have suggested that ginkgo may also protect against the toxic effects of β-amyloid. Although previous clinical trials of ginkgo leaf extracts have had mixed results, many older people continue to use the herb in the hope of warding off the onset of Alzheimer’s disease. The new study, however, has shown that ginkgo gave no benefit in reducing all-cause dementia or Alzheimer’s dementia. The study involved more than 3000 men and women aged 75 or older who were randomised to placebo or treatment groups. The treated group received 120mg ginkgo twice a day for an average of 6 years. At the end of the study, dementia developed in 246 people taking ginkgo compared with 277 people in the placebo group. The authors note that an effect may have been seen had the study carried on for longer since it is known that there is a significant time lag between initial brain changes and the manifestation of clinical dementia.

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