Strategies for disease modification in Alzheimer's disease

Treating Alzheimer's disease (AD) is the biggest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. Three main classes of disease-modification approaches can be defined: one that is broadly neurotrophic or neuroprotective, one that targets specific aspects of AD pathology, and one that is based on epidemiological observation. This review discusses all three approaches, with particular emphasis on anti-amyloid strategies - currently the most active area of investigation. The approaches that are reviewed include secretase inhibition, amyloid-beta aggregation inhibition, immunotherapy and strategies that might indirectly affect the amyloid pathway.     

Human disease: calcium signaling in polycystic kidney disease

Polycystic kidney disease results from loss of function of either of two novel proteins, polycystin-1 or polycystin-2. Recent studies show that intracellular calcium signaling is important in kidney development, and define defects in this signaling pathway as the basis of cyst formation in polycystic kidney disease.     

Borna disease virus in mice: host-specific differences in disease expression.

We developed a mouse model of Borna disease to facilitate immunopathogenesis research by adaptation of Borna disease virus to mice through serial passage in mouse brain tissue. Borna disease virus replication, antibody production, inflammation, and Borna disease expression in several different strains of mice were examined.     

Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease

In searching for a putative third gene for autosomal dominant polycystic kidney disease (ADPKD), we studied the genetic inheritance of a large family (NFL10) previously excluded from linkage to both the PKD1 locus and the PKD2 locus. We screened 48 members of the NFL10 pedigree, by ultrasonography, and genotyped them, with informative markers, at both the PKD1 locus and the PKD2 locus. Twenty-eight of 48 individuals assessed were affected with ADPKD. Inspection of the haplotypes of these individuals suggested the possibility of bilineal disease from independently segregating PKD1 and PKD2 mutations. Using single-stranded conformational analysis, we screened for and found a PKD2 mutation (i.e., 2152delA; L736X) in 12 affected pedigree members. Additionally, when the disease status of these individuals was coded as "unknown" in linkage analysis, we also found, with markers at the PKD1 locus, significant LOD scores (i.e., >3.0). These findings strongly support the presence of a PKD1 mutation in 15 other affected pedigree members, who lack the PKD2 mutation. Two additional affected individuals had trans-heterozygous mutations involving both genes, and they had renal disease that was more severe than that in affected individuals who had either mutation alone. This is the first documentation of bilineal disease in ADPKD. In humans, trans-heterozygous mutations involving both PKD1 and PKD2 are not necessarily embryonically lethal. However, the disease associated with the presence of both mutations appears to be more severe than the disease associated with either mutation alone. The presence of bilineal disease as a confounder needs to be considered seriously in the search for the elusive PKD3 locus.     

IL-6 in autoimmune disease and chronic inflammatory proliferative disease

Interleukin 6 (IL-6), which was originally identified as a B-cell differentiation factor, is now known to be a multifunctional cytokine that regulates the immune response, hematopoiesis, the acute phase response, and inflammation. Deregulation of IL-6 production is implicated in the pathology of several disease processes. The expression of constitutively high levels of IL-6 in transgenic mice results in fatal plasmacytosis, which has been implicated in human multiple myeloma. Increased IL-6 levels are also observed in several diseases, including rheumatoid arthritis (RA), systemic-onset juvenile chronic arthritis (JCA), osteoporosis, and psoriasis. IL-6 is critically involved in experimentally induced autoimmune disease, such as antigen-induced arthritis (AIA), and experimental allergic encephalomyelitis. All these clinical data and animal models suggest that IL-6 plays critical roles in the pathogenesis of autoimmune diseases. Here we review the evidence for the involvement of IL-6 in the pathophysiology of autoimmune diseases and chronic inflammatory proliferative diseases (CIPD) and discuss the possible molecular mechanisms of its involvement.     

Metallostasis in Alzheimer's disease

2012 has been another year in which multiple large-scale clinical trials for Alzheimer's disease (AD) have failed to meet their clinical endpoints. With the social and financial burden of this disease increasing every year, the onus is now on the field of AD researchers to investigate alternative ideas to deliver outcomes for patients. Although several major clinical trials targeting Aβ have failed, three smaller clinical trials targeting metal interactions with Aβ have all shown benefit for patients. Here we review the genetic, pathological, biochemical, and pharmacological evidence that underlies the metal hypothesis of AD. The AD-affected brain suffers from metallostasis, or fatigue of metal trafficking, resulting in redistribution of metals into inappropriate compartments. The metal hypothesis is built upon a triad of transition elements: iron, copper, and zinc. The hypothesis has matured from early investigations showing amyloidogenic and oxidative stress consequences of these metals; recently, disease-related proteins, APP, tau, and presenilin, have been shown to have major roles in metal regulation, which provides insight into the pathway of neurodegeneration in AD and illuminates potential new therapeutic avenues.     

Monocytes in Hodgkin's disease

It should be stated, there exist many abnormalities of monocytes function in HD patients, while examined in vitro. Their biological significance in vivo remains to be elucidated. The disturbances of monocyte-macrophage system certainly influence the immunoregulation mechanism, especially T-cell-macrophage cooperation and this way augment the immune deficite observed in patients with HD, increase their susceptibility to infections and may be an additional factor favoring tumour dissemination, particularly in the advanced stages of the disease.     

Autophagy in cardiovascular disease

Autophagy is a major cytoprotective pathway that eukaryotic cells use to degrade and recycle cytoplasmic contents. Recent evidence indicates that autophagy under baseline conditions represents an important homeostatic mechanism for the maintenance of normal cardiovascular function and morphology. By contrast, excessive induction of the autophagic process by environmental or intracellular stress has an important role in several types of cardiomyopathy by functioning as a death pathway. As a consequence, enhanced autophagy represents one of the mechanisms underlying the cardiomyocyte dropout responsible for the worsening of heart failure. Successful therapeutic approaches that regulate autophagy have been reported recently, suggesting that the autophagic machinery can be manipulated to treat heart failure or to prevent rupture of atherosclerotic plaques and sudden death.