A diverse portfolio of novel drug discovery efforts for Alzheimer's disease: Meeting report from the 11th International Conference on Alzheimer's Drug Discovery, 27-28 September 2010, Jersey City, NJ, USA

While Alzheimer's disease researchers continue to debate the underlying cause(s) of the disease, most agree that a diverse, multi-target approach to treatment will be necessary. To this end, the Alzheimer's Drug Discovery Foundation (ADDF) recently hosted the 11th International Conference on Alzheimer's Drug Discovery to highlight the array of exciting efforts from the ADDF's funded investigators

Beyond amyloid: a diverse portfolio of novel drug discovery programs for Alzheimer's disease and related dementias

Although the molecular mechanisms underlying the pathogenesis of Alzheimer's disease and other related neurodegenerative diseases remain unclear, accumulation of misfolded proteins, neuroinflammation, mitochondrial dysfunction and perturbed calcium homeostasis have been identified as key events leading to neuronal loss during neurodegeneration. Evidence for 'druggable' targets for each of these key mechanisms was presented by the Alzheimer's Drug Discovery Foundation-funded investigators at the 12th International Conference on Alzheimer's Drug Discovery, Jersey City, NJ, 26-27 September 2011 http://www.worldeventsforum.com/addf/addrugdiscovery

Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size

Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1−/− mice, which display a proportional decrease in the sizes of all organs, Akt3−/− mice present a selective 20% decrease in brain size. Moreover, although Akt1- and Akt3-deficient brains are reduced in size to approximately the same degree, the absence of Akt1 leads to a reduction in cell number, whereas the lack of Akt3 results in smaller and fewer cells. Finally, mammalian target of rapamycin signaling is attenuated in the brains of Akt3−/− but not Akt1−/− mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth

Exploring the Nexus of Alzheimer’s Disease and Related Dementias with Cancer and Cancer Therapies

Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer’s disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation convened a one day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations and partnerships for future action

Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies

Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable

Signaling pathways regulating amyloid precursor protein and Abeta generation: Roles for isoprostane-induced thromboxane receptor signaling and chronic Akt activation in Alzheimer\u27s disease

Alzheimer\u27s disease (AD) is a neurodegenerative disease pathologically marked by neurofibrillary tangles, senile plaques, inflammation, and oxidative stress ultimately culminating in neuronal cell loss. Senile plaques are composed of aggregated amyloid-β (Aβ) peptides, which are cleaved from a larger protein known as the amyloid precursor protein (APP). The regulation of APP and Aβ generation is thought to be the central initiator of AD pathogenesis. Consequently, modulation of this pathway is of therapeutic importance for AD. Both cardiovascular disease and diabetes increase risk for AD and share many common risk factors with AD. These diseases also share common disease modifying pathways. In the work outlined here, two signaling pathways involved in cardiovascular disease and diabetes are linked to APP metabolism, Aβ generation and amyloid pathology. Isoprostanes, products of lipid peroxidation, are elevated in conditions of oxidative stress, such as heart disease and diabetes and are also elevated in human AD patients and mouse models of AD. The isoprostane isoform, iPF2α-III, can activate the thromboxane (TP) receptor and promote atherosclerotic plaque formation in cardiovascular disease. Our studies show that iPF2α-III-induced TP receptor activation can also promote AD amyloid pathology in mice by initiating downstream signaling events that post-transcriptionally stabilize APP mRNA, resulting in more substrate for the proteolytic cleavage reactions that generate Aβ. TP receptor antagonists have been developed for the treatment of cardiovascular disease. Here, we used both rational design and high throughput screening to develop brain penetrable TP receptor antagonists that may also be therapeutically beneficial for AD. Insulin signaling, which is impaired in insulin resistance and type 2 diabetes, can also regulate trafficking and secretion of APP. Our work demonstrates that chronic activation of Akt, a downstream mediator of the insulin signaling pathway, can cause feedback inhibition of this pathway and lead to defects in trafficking of APP and APP metabolites. Both TP receptor activation and insulin signaling, in addition to their known roles in cardiovascular disease and diabetes, can also regulate APP at many levels along its biogenesis and metabolism and ultimately influence AD pathology

Signaling pathways regulating amyloid precursor protein and Abeta generation: Roles for isoprostane-induced thromboxane receptor signaling and chronic Akt activation in Alzheimer\u27s disease

Alzheimer\u27s disease (AD) is a neurodegenerative disease pathologically marked by neurofibrillary tangles, senile plaques, inflammation, and oxidative stress ultimately culminating in neuronal cell loss. Senile plaques are composed of aggregated amyloid-β (Aβ) peptides, which are cleaved from a larger protein known as the amyloid precursor protein (APP). The regulation of APP and Aβ generation is thought to be the central initiator of AD pathogenesis. Consequently, modulation of this pathway is of therapeutic importance for AD. Both cardiovascular disease and diabetes increase risk for AD and share many common risk factors with AD. These diseases also share common disease modifying pathways. In the work outlined here, two signaling pathways involved in cardiovascular disease and diabetes are linked to APP metabolism, Aβ generation and amyloid pathology. Isoprostanes, products of lipid peroxidation, are elevated in conditions of oxidative stress, such as heart disease and diabetes and are also elevated in human AD patients and mouse models of AD. The isoprostane isoform, iPF2α-III, can activate the thromboxane (TP) receptor and promote atherosclerotic plaque formation in cardiovascular disease. Our studies show that iPF2α-III-induced TP receptor activation can also promote AD amyloid pathology in mice by initiating downstream signaling events that post-transcriptionally stabilize APP mRNA, resulting in more substrate for the proteolytic cleavage reactions that generate Aβ. TP receptor antagonists have been developed for the treatment of cardiovascular disease. Here, we used both rational design and high throughput screening to develop brain penetrable TP receptor antagonists that may also be therapeutically beneficial for AD. Insulin signaling, which is impaired in insulin resistance and type 2 diabetes, can also regulate trafficking and secretion of APP. Our work demonstrates that chronic activation of Akt, a downstream mediator of the insulin signaling pathway, can cause feedback inhibition of this pathway and lead to defects in trafficking of APP and APP metabolites. Both TP receptor activation and insulin signaling, in addition to their known roles in cardiovascular disease and diabetes, can also regulate APP at many levels along its biogenesis and metabolism and ultimately influence AD pathology