Roles have been suggested for brain-derived neurotrophic factor (BDNF) – which helps to support neurons and also stimulates and controls neurogenesis – in preventing or treating degenerative diseases such amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. The use of BDNF itself in therapy is limited by a poor pharmokinetic profile including rapid metabolism and poor CNS penetration. BDNF elicits at least some of its effects through binding to the high affinity tyrosine kinase receptor B, TrkB, and investigators at Emory University School of Medicine have now identified a small, high-affinity molecule that can also activate signalling through TrkB.

7,8-Dihydroxyflavone was shown to protect wild-type, but not TrkB-deficient, neurons from apoptosis. Following intraperitoneal administration, the compound was also found to activate TrkB in the brain and to be protective in animal models of seizure, stroke and Parkinson’s disease. The compound was also found to have low toxicity on chronic dosing. Although favonoids such as 7,8-dihydroxyflavone occur in a wide range of foodstuffs, levels obtained from a normal diet are believed to be insufficient for a sustained effect.

The study is published in the online early edition of PNAS.

Neurofibrillary tangles (NFT) are a hallmark of Alzheimer’s disease (AD) and correlate strongly with synaptic loss and severity of dementia. NFT appear to be attributable, at least in part, to hyperphosphorylation of the microtubule-stabilising protein, tau. Numerous phosphorylation sites have been associated with tau dysfunction and neurodegeneration: phosphorylation on Ser²⁶² has been shown to occur early in disease progression and to significantly reduce the affinity of tau for microtubules. Although hyperphosporylation at other sites is likely necessary for neurodegeneration, increased phosphorylation at Ser²⁶² is an important early step and firm identification of the kinase(s) responsible for phosphorylation at this position could provide new targets for disease-modifying treatments. Numerous kinases have been reported to phosphorylate tau at Ser²⁶² in vitro, but the role of these kinases on neurofibrillary tangle formation in vivo remains unclear.

Using a loss of function high throughput RNAi approach to screen the entire human kinome, a team led by scientists at the Translational Genomics Research Institute (TGen) have now identified three new kinases, dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), A-kinase anchor protein 13 (AKAP13), and eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) that contribute to hyperphosphorylation of tau. Whereas DYRK1A and AKAP13 appear to be specifically involved in tau phosphorylation pathways, the effects of EIF2AK2 may result from alterations in tau protein expression.

If further studies in neuronal cell lines and in vivo models of AD and tauopathies confirm the importance of these kinases in disease pathology, they would represent novel targets for disease-modifying treatments for AD.

The study is published in BMC Genomics.

Prion diseases comprise the transmissible spongiform encephalopathies, including scrapie in sheep, bovine spongiform encephalopathy (BSE, “Mad Cow” disease) in cattle and Creutzfeldt-Jakob disease in humans. Central to these diseases is the conversion of normal cellular prion protein (PrP^c) into the abnormally folded, pathogenic species (PrP^Sc) in the brain. The misfolding results in prion protein with distinct biochemical properties compared to the normal protein, such as reduced solubility and decreased susceptibility to proteases. Aggregates of PrP^Sc accumulate in association with neurons in affected brain areas, which is thought to lead to the synapse degeneration and neuronal death observed in infected hosts.

Researchers in the UK and Italy have now shown that glimepiride, a sulfonyl urea approved for the treatment of non insulin dependent diabetes mellitus (NIDDM), is able to reduce PrP^Sc formation in cell culture. The rationale for the study was based on the knowledge that generation of PrP^Sc is dependent on the presence of PrP^c and that this appeared to require PrPc expressed at the cell surface. PrP^c is linked to the membrane by a glycosylphosphatidylinositol (GPI) anchor and can be released from the surface of cells by treatment with phosphatidylinositol-phospholipase C (PI-PLC). Consistent with the hypothesis that cell-surface PrP^c is required, treatment of prion-infected neuronal cells with PI-PLC reduced PrP^Sc formation.

Since glimepiride has been shown to stimulate the release of some GPI-anchored proteins in adipocytes (via stimulation of an endogenous GPI-PLC), the team explored the effects of the drug on PrP^c/PrP^Sc in neuronal cell culture. Similarly to PI-PLC, glimepiride reduced the amount of cell-surface PrP^c in primary cortical neurons and neuronal cell lines. In addition, glimepiride reduced formation of PrP^Sc in three prion-infected neuronal cell lines.

The study, published in PLoSone, also demonstrated that glimepiride treated neurons were resistant to the toxicity of a PrP-derived peptide, PrP82-146.

The team note that modulation of cell-surface PrP^c may also have application in Alzheimer’s disease since it is a receptor for β-amyloid oligomers. Whether glimepiride is sufficiently CNS-penetrant to be effective remains to be seen.

Although family history and lifestyle choices play a role, ageing is recognised to be the largest single risk factor for Alzheimer’s disease. Progression of Alzheimer’s disease is not well understood but accumulation of toxic amyloid peptides in the brain is believed to be a significant contributory factor and much research has focussed on reducing levels of these peptides. Researchers led by a team at the Salk Institute have now asked whether slowing the ageing progress might also delay the onset of Alzheimer’s disease. The insulin/insulin growth factor (IGF) signalling (IIS) pathway regulates stress resistance, and reduction of IIS has been shown to increase lifespan in worms, flies, and mice. Although reduced IGF signalling extends the life span of mice, IGF-1 infusion has also been shown to protect mice against amyloid toxicity. To address this apparent paradox, the team crossed mice that model Alzheimer’s disease with long-lived mice that have reduced IGF signalling. The animals were found to be protected from Alzheimer’s disease-like symptoms, including behavioural impairment, neuroinflammation, and neuronal loss. Although the mice continued to produce amyloid peptides, these were found to form densely packed, ordered plaques, suggesting that hyper-aggregation of more toxic soluble amyloid oligomers may explain, at least in part, the protection conferred by reduced IGF signalling.

Although previous studies have shown that IGF-1 infusion protects mice against amyloid toxicity, the growth hormone secretagogue MK-677 (ibutamoren mesylate), a potent inducer of IGF-1 secretion, was ineffective at slowing the rate of progression of Alzheimer’s disease in human patients.

IIS reduction has been found to correlate with longevity in humans – some very long-lived people have defects in components of IIS – and the present study, which is published in the journal Cell, suggests that reduction in IGF-1 signalling may be a promising strategy for the treatment of Alzheimer’s disease.

Amyloid plaques, which deposit around nerve cells, and neurofibrillary tangles, which build up inside the cells, are the primary hallmarks of Alzheimer’s disease. Many researchers believe that the plaques trigger a cascade of events leading to disease pathology but, although this hypothesis is supported by animal studies, it has not been conclusively proved in humans. Amyloid deposition has also been suggested to lead to neuroinflammation, creating a positive feedback loop resulting in further amyloid accumulation and chronic inflammation. Polymorphisms leading to increased levels of interleukin-6 (IL-6), a pro-inflammatory cytokine which activates microglial cells, have been linked to Alzheimer’s disease, adding weight to this hypothesis.

Scientists at the Mayo Clinic were carrying out experiments to demonstrate that activated microglia exacerbate neurodegeneration when they discovered, unexpectedly, that the microglia cleared the plaques from the brain. They had believed that the microglia would be unable to clear the plaques and that the resulting inflammation would worsen the disease. To examine the effect of IL-6 on amyloid processing and deposition, the team over-expressed murine IL-6 (mIL-6) in the brains of transgenic mice expressing mutated forms of the human amyloid precursor protein. Instead of creating a neurotoxic feedback loop that exacerbated amyloid pathology, IL-6 had no effect on amyloid processing and enhanced plaque clearance.

The study, which was published online on October 14^th in the FASEB Journal, is the first to examine in detail the effect of mIL-6 on amyloid deposition in vivo and suggests that the use of inflammatory mediators to manipulate the immune response could lead to new therapeutic approaches for the treatment of neurodegenerative diseases such as Alzheimer’s disease.

A study by researchers at the Universities of Florida and Frankfurt, published earlier this year in the journal Acta Neuropathologica, also addressed the role of microglia in Alzheimer’s disease. The study showed that microglia in amyloid-laden, degenerating regions of the brains of Alzheimer’s disease patients are not activated but, instead, are senescent and dystrophic. The team suggest that loss of microglia may contribute to neurodegeneration and that finding ways to keep microglia alive and healthy would be better than trying to inhibit their function with anti-inflammatory drugs.

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.

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.

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.

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.

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.