http://alzres.com The latest research articles published by Alzheimer's Research & Therapy 2013-05-21T00:00:00Z Genetic studies have provided the best evidence for cause and effect relationships in Alzheimer's disease (AD). Indeed, the identification of deterministic mutations in the APP, PSEN1 and PSEN2 genes and subsequent preclinical studies linking these mutations to alterations in Aβ production and aggregation have provided pivotal support for the amyloid cascade hypothesis. In addition, genetic, pathologic and biological studies of APOE have also indicated that the genetic risk for AD associated with APOE4 can be attributed, at least in part, to its pro-amyloidogenic effect on Aβ. In recent years a number of SNPs that show unequivocal genome-wide association with AD risk have implicated novel genetic loci as modifiers of AD risk. However, the functional implications of these genetic associations are largely unknown. For almost all of these associations, the functional variants have not been identified. Very recently, two large consortiums demonstrated that rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene confer significant risk for AD. TREM2 is a type 1 membrane receptor protein primarily expressed on microglia in the central nervous system that has been shown to regulate phagocytosis and activation of monocytes. Previously it had been shown that homozygous loss of function mutations in TREM2 cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, Nasu Hakola disease) and also a pure form of early-onset dementia. The association of TREM2 variants with AD brings innate immune signaling into the light, affirming innate immunity's role as a significant factor in AD pathogenesis. http://alzres.com/content/5/3/24 Todd Golde Wolfgang Streit Paramita Chakrabarty Alzheimer's Research & Therapy 2013, null:24 2013-05-21T00:00:00Z doi:10.1186/alzrt178 TREM2 variants and AD risk <p>Golde and colleagues review the function of innate immune signalling in Alzheimer's disease (AD) following recent studies showing variants of TREM2, a triggering receptor on myeloid cells, is significantly associated with AD risk.</p> /content/figures/alzrt178-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 24 2013-05-21T00:00:00Z XML Addressing causes of heterogeneity in cognitive outcomes is becoming more critical as Alzheimer's disease (AD) research focuses on earlier disease. One of the causes of this heterogeneity may be that individuals with deficiencies in different cognitive domains may perform similarly on a neuropsychological (NP) test for very different reasons. Tatsuoka and colleagues have applied a Bayesian model in order to integrate knowledge about cognitive domains relevant to each NP test with the observed outcomes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) mild cognitive impairment data. This approach resulted in better prediction of AD diagnosis than more traditional approaches. http://alzres.com/content/5/3/22 Suzanne Hendrix Kathleen Welsh-Bohmer Alzheimer's Research & Therapy 2013, null:22 2013-05-15T00:00:00Z doi:10.1186/alzrt176 /content/figures/alzrt176-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 22 2013-05-15T00:00:00Z XML IntroductionDespite years of research, there are no disease-modifying drugs for Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. Screening for potential therapeutics in rodent models of AD has generally relied on testing compounds before pathology is present, thereby modeling disease prevention rather than disease modification. Furthermore, this approach to screening does not reflect the clinical presentation of AD patients which could explain the failure to translate compounds identified as beneficial in animal models to disease modifying compounds in clinical trials. Clearly a better approach to pre-clinical drug screening for AD is required. Methods: To more accurately reflect the clinical setting, we used an alternative screening strategy involving the treatment of AD mice at a stage in the disease when pathology is already advanced. Aged (20-month-old) transgenic AD mice (APP/swePS1[increment]E9) were fed an exceptionally potent, orally active, memory enhancing and neurotrophic molecule called J147. Cognitive behavioral assays, histology, ELISA and Western blotting were used to assay the effect of J147 on memory, amyloid metabolism and neuroprotective pathways. J147 was also investigated in a scopolamine-induced model of memory impairment in C57Bl/6J mice and compared to donepezil. Details on the pharmacology and safety of J147 are also included. Results: Data presented here demonstrate that J147 has the ability to rescue cognitive deficits when administered at a late stage in the disease. The ability of J147 to improve memory in aged AD mice is correlated with its induction of the neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) as well as several BDNF-responsive proteins which are important for learning and memory. The comparison between J147 and donepezil in the scopolamine model showed that while both compounds were comparable at rescuing short term memory, J147 was superior at rescuing spatial memory and a combination of the two worked best for contextual and cued memory. Conclusion: J147 is an exciting new compound that is extremely potent, safe in animal studies and orally active. J147 is a potential AD therapeutic due to its ability to provide immediate cognition benefits, and it also has the potential to halt and perhaps reverse disease progression in symptomatic animals as demonstrated in these studies. http://alzres.com/content/5/3/25 Marguerite Prior Richard Dargusch Jennifer Ehren Chandramouli Chiruta Dave Schubert Alzheimer's Research & Therapy 2013, null:25 2013-05-14T00:00:00Z doi:10.1186/alzrt179 Improving memory in AD mice <p>Novel drug candidate J147 is able to arrest and reverse memory deficits and improve several aspects of brain function in aged mice with advanced symptoms of Alzheimer's disease (AD).</p> /content/figures/alzrt179-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 25 2013-05-14T00:00:00Z PDF Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for the majority of dementia cases. While research over the past decades has made advances into understanding disease pathology, definite AD diagnosis currently relies on confirmation by autopsy. The anticipated dramatic rise in affected individuals over the next decades necessitates the development of diagnostic tests applicable to living individuals, which depends on identification of disease biomarkers. Diagnostics based on blood protein biomarkers are particularly desired since these would allow for economical, rapid and non-invasive analysis of individual biomarker profiles. Research is actively ongoing in this field and has led to the identification of autoantibodies and various proteins in the blood that may represent a disease-specific blood signature of AD. This review provides an overview on the progress in the field of identification of AD-specific blood protein biomarkers. http://alzres.com/content/5/3/18 Lorraine Clark Thomas Kodadek Alzheimer's Research & Therapy 2013, null:18 2013-05-09T00:00:00Z doi:10.1186/alzrt172 Diagnosing AD before autopsy <p>Clark and Kodadek review the current progress to identify Alzheimer's disease (AD)-specific blood-based protein biomarkers, which would allow for an economical, rapid and non-invasive diagnostic test for the disease.</p> /content/figures/alzrt172-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 18 2013-05-09T00:00:00Z XML Alzheimer's disease (AD), for which there is no cure, is the most common form of dementia in the elderly. Despite tremendous efforts by the scientific community, the AD drug development pipeline remains extremely limited. Animal models of disease are a cornerstone of any drug development program and should be as relevant as possible to the disease, recapitulating the disease phenotype with high fidelity, to meaningfully contribute to the development of a successful therapeutic agent. Over the past two decades, transgenic models of AD based on the known genetic origins of familial AD have significantly contributed to our understanding of the molecular mechanisms involved in the onset and progression of the disease. These models were extensively used in AD drug development. The numerous reported failures of new treatments for AD in clinical trials indicate that the use of genetic models of AD may not represent the complete picture of AD in humans and that other types of animal models relevant to the sporadic form of the disease, which represents 95% of AD cases, should be developed. In this review, we will discuss the evolution of non-transgenic rat models of AD and how these models may open new avenues for drug development. http://alzres.com/content/5/3/17 Laurent Lecanu Vassilios Papadopoulos Alzheimer's Research & Therapy 2013, null:17 2013-05-01T00:00:00Z doi:10.1186/alzrt171 Non-transgenic rat models and AD <p>Lecanu and Papadopoulos discuss pharmacologically induced rat models of sporadic Alzheimer's disease (AD) and their potential benefits for drug development over transgenic alternatives.</p> /content/figures/alzrt171-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 17 2013-05-01T00:00:00Z XML The Alzheimer's disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. There is growing awareness that clinical trials must target stage-appropriate pathophysiological mechanisms to effectively develop disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in amyloid-beta (Aβ), brain metabolism and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. These findings suggest that amyloid-based therapies would optimally be targeted at the earliest clinically detectable stage (such as mild cognitive impairment (MCI)) or before. Postmortem data indicate that tau lesions in the locus coeruleus (LC), the primary source of subcortical norepinephrine (NE), may be the first identifiable pathology of AD, and recent data from basic research in animal models of AD indicate that loss of NE incites a neurotoxic proinflammatory condition, reduces Aβ clearance and negatively impacts cognition - recapitulating key aspects of AD. In addition, evidence linking NE deficiency to neuroinflammation in AD also exists. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing Aβ degradation and clearance, LC degeneration and NE loss can be considered a triple threat to AD pathogenesis. Remarkably, restoration of NE reverses these effects and slows neurodegeneration in animal models, raising the possibility that treatments which increase NE transmission may have the potential to delay or reverse AD-related pathology. This review describes the evidence supporting a key role for noradrenergic-based therapies to slow or prevent progressive neurodegeneration in AD. Specifically, since MCI coincides with the onset of clinical symptoms and brain atrophy, and LC pathology is already present at this early stage of AD pathogenesis, MCI may offer a critical window of time to initiate novel noradrenergic-based therapies aimed at the secondary wave of events that lead to progressive neurodegeneration. Because of the widespread clinical use of drugs with a NE-based mechanism of action, there are immediate opportunities to repurpose existing medications. For example, NE transport inhibitors and NE-precursor therapies that are used for treatment of neurologic and psychiatric disorders have shown promise in animal models of AD, and are now prime candidates for early-phase clinical trials in humans. http://alzres.com/content/5/2/21 Termpanit Chalermpalanupap Becky Kinkead William Hu Markus Kummer Thea Hammerschmidt Michael Heneka David Weinshenker Allan Levey Alzheimer's Research & Therapy 2013, null:21 2013-04-29T00:00:00Z doi:10.1186/alzrt175 Targeting norepinephrine <p>Treatments that increase norepinephrine transmission and may have the potential to delay or reverse Alzheimer's disease-related pathology are discussed by Levey and colleagues, who review the evidence for noradrenergic-based therapies.</p> /content/figures/alzrt175-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 21 2013-04-29T00:00:00Z XML During the past 20 years, the 5-HT6 receptor has received increasing attention and become a promising target for improving cognition. Several studies with structurally different compounds have shown that not only antagonists but also 5-HT6 receptor agonists improve learning and memory in animal models. A large number of publications describing the development of ligands for this receptor have come to light, and it is now quite evident that 5-HT6 receptors have great pharmaceutical potential in terms of related patents. However, 5-HT6 receptor functionality is much more complex than initially defined. According to the existing data, different cellular pathways may be activated, depending on the drug being used. This article reviews preclinical and clinical evidence of the effects that 5-HT6 receptor compounds have on cognition. In addition, the biochemical and neurochemical mechanisms of action through which 5-HT6 receptor compounds can influence cognition will be described. Overall, several 5-HT6-targeted compounds can reasonably be regarded as powerful drug candidates for the treatment of Alzheimer's disease. http://alzres.com/content/5/2/15 María Ramírez Alzheimer's Research & Therapy 2013, null:15 2013-04-22T00:00:00Z doi:10.1186/alzrt169 5-HT6 receptors and AD <p>Mar&iacute;a Javier Ram&iacute;rez reviews evidence supporting the cognitive effects of 5-HT₆ receptor compounds, resulting in 5-HT₆-targeted compounds being regarded as powerful therapeutic candidates in Alzheimer's disease (AD).</p> /content/figures/alzrt169-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 15 2013-04-22T00:00:00Z XML IntroductionType 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). An impairment of insulin signaling as well as a desensitization of its receptor has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP) normalises insulin signaling by facilitating insulin release. GIP directly modulates neurotransmitter release, LTP formation, and protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation, and cell proliferation of progenitor cells in the dentate gyrus. Here we investigate the potential therapeutic property of the new long lasting incretin hormone analogue D-Ala2GIP on key symptoms found in a mouse model of Alzheimer' disease (APPswe/PS1detaE9). Methods: D-Ala2GIP was injected for 21 days at 25 nmol/kg ip once daily in APP/PS1 male mice and wild type (WT) littermates aged 6 or 12 months of age. Amyloid plaque load, inflammation biomarkers, synaptic plasticity in the brain (LTP), and memory were measured. Results: D-Ala2GIP improved memory in WT mice and rescued the cognitive decline of 12 months old APP/PS1 mice in two different memory tasks. Furthermore, deterioration of synaptic function in the dentate gyrus and cortex was prevented in 12 months old APP/PS1 mice. D-Ala2GIP facilitated synaptic plasticity in APP/PS1 and WT mice and reduced the number of amyloid plaques in the cortex of D-Ala2GIP injected APP/PS1 mice. The inflammatory response in microglia was also reduced. Conclusion: The results demonstrate that D-Ala2GIP has neuroprotective properties on key hallmarks found in AD. This finding shows that novel GIP analogues have the potential as a novel therapeutic for AD. http://alzres.com/content/5/2/20 Emilie Faivre Christian Holscher Alzheimer's Research & Therapy 2013, null:20 2013-04-19T00:00:00Z doi:10.1186/alzrt174 Neuroprotective effects of D-Ala2GIP <p>A new long-lasting analogue of glucose-dependent insulinotropic polypeptide (GIP) has neuroprotective properties including rescuing cognitive performance and reducing Abeta plaque load and neuroinflammation in an animal model of Alzheimer's disease.</p> /content/figures/alzrt174-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 20 2013-04-19T00:00:00Z XML IntroductionModulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Aβ42 peptide while sparing the production of other Aβ species, is a promising therapeutic approach for the treatment of Alzheimer's disease. Satori has identified a unique class of small molecule gamma-secretase modulators (GSMs) capable of decreasing Aβ42 levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Aβ42 and Aβ38 while sparing Aβ40 and total Aβ levels. In vivo, a compound from the series, SPI-1865, demonstrates similar pharmacology in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats. Methods: Animals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aβ levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS. Results: In wild-type mice using either dosing regimen, brain Aβ42 and Aβ38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ40 was observed, reflecting the changes observed in vitro. In rats, brain Aβ levels were examined and similar to the mouse studies, brain Aβ42 and Aβ38 were lowered. Comparable changes were also observed in the Tg2576 mice, where Aβ levels were measured in brain as well as plasma and CSF. Conclusions: Taken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aβ42 in a dose responsive manner. With this unique profile, the class of compounds represented by SPI-1865 may be a promising new therapy for Alzheimer's disease. http://alzres.com/content/5/2/19 Robyn Loureiro Jo Ann Dumin Timothy McKee Wesley Austin Nathan Fuller Jed Hubbs Ruichao Shen Jeff Jonker Jeff Ives Brian Bronk Barbara Tate Alzheimer's Research & Therapy 2013, null:19 2013-04-18T00:00:00Z doi:10.1186/alzrt173 Novel GSM shows promise for AD <p>A novel gamma-secretase modulator (GSM) and promising new therapy in Alzheimer&rsquo;s disease (AD) is orally bioavailable, brain penetrant, and effective at lowering Abeta42 in a dose responsive manner in multiple rodent models.</p> /content/figures/alzrt173-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 19 2013-04-18T00:00:00Z XML The pathological hallmark of Alzheimer's disease (AD), the leading cause of senile dementia, involves region-specific neuronal death and an accumulation of neuronal and extracellular lesions termed neurofibrillary tangles and senile plaques, respectively. One of the biochemical abnormalities observed in AD is reduced DNA end-joining activity. The reduced capacity of post-mitotic neurons for some types of DNA repair is further compromised by aging. The predominant mechanism to repair double-strand DNA (dsDNA) breaks (DSB) is non-homologous end joining (NHEJ), which requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK is a holoenzyme comprising the p460 kDa DNA-PK catalytic subunit (DNA-PKcs) and the Ku heterodimer consisting of p86 (Ku 80) and p70 (Ku 70) subunits. Ku binds to DNA ends first and then recruits DNA-PKcs during NHEJ. However, in AD brains, reduced NHEJ activity has been reported along with reduced levels of DNA-PKcs and the Ku proteins, indicating a potential link between AD and dsDNA damage. Since age-matched control brains also show a reduction in these protein levels, whether there is a direct link between NHEJ ability and AD remains unknown. Possible mechanisms involving the role of DNA-PK in neurodegeneration, a benchmark of AD, are the focus of this review. http://alzres.com/content/5/2/13 Jyotshna Kanungo Alzheimer's Research & Therapy 2013, null:13 2013-04-08T00:00:00Z doi:10.1186/alzrt167 DNA-PK in neurodegeneration <p>Jyotshna Kanungo discusses possible mechanisms for the role of DNA-dependent protein kinase (DNA-PK) in neurodegeneration leading to Alzheimer's disease.</p> /content/figures/alzrt167-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 13 2013-04-08T00:00:00Z XML