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Vascular Pathology in Familial Alzheimer Disease

A group led by Dr. Gregory A. Elder of the James J. Peters Veteran's Affairs Medical Center, Bronx, NY has demonstrated that presenilin-1 plays a role in the vascular pathology found in Alzheimer disease. Their report can be found in the January 2010 issue of the American Journal of Pathology.

Alzheimer disease accounts for half of all dementias diagnosed each year. Mutations in presenilin-1 (PS-1), which cleaves amyloid precursor protein, are one of the most common causes of early onset cases of familial Alzheimer disease (FAD), which accounts for 5-10% of all Alzheimer disease sufferers.

Alzheimer disease is accompanied by vascular pathology, where blood vessels and microvessels are damaged. To determine if mutated PS-1 contributes to the vascular pathology observed in FAD, Gama Sosa et al generated a mouse model that overexpressed either wild-type or mutated human PS-1. They found age-related vascular pathology in these FAD model mice that was especially prominent in the microvasculature. However, the basis for this pathology appears to lie in the neurons, as neurons but not vascular endothelial or glial cells express PS-1 in these mice. Taken together, these results implicate a role for neuronal to vascular signaling in the pathogenesis of vascular pathology in FAD.

In future studies, Dr. Elder and colleagues plan to use their mouse model to "uncover the role of PS-1 FAD mutants in neurovascular signaling and provide insights into how neurovascular signaling may be disrupted in sporadic [Alzheimer disease] as well."

Gama Sosa MA, De Gasperi R, Rocher AB, Wang AC-J, Janssen WGM, Flores T, Perez GM, Schmeidler J: Age-Related Vascular Pathology in Transgenic Mice Expressing Presenilin 1-Associated Familial Alzheimer's Disease Mutations. Am J Pathol 2010, 176: 353-368

Osteopontin Contributes to Allergic Contact Dermatitis

Dr. Johannes M. Weiss and colleagues at the University of Ulm, Ulm, Germany have discovered that osteopontin (OPN) contributes to allergic contact dermatitis. They present these findings in the January 2010 issue of the American Journal of Pathology.

Allergic contact dermatitis is a hyperreaction of the immune system to either allergens or irritants on the skin, such as poison ivy, nickel, or latex. Contact dermatitis results in large, burning, and itchy rashes, which can take anywhere from several days to weeks to heal. Once allergic contact dermatitis occurs, only strict avoidance can prevent a recurrence, and there is no method to resist persistent sensitization.

Seier et al hypothesized that OPN, an immune mediator that has been shown to worsen the effects of autoimmune disease, played a role in eliciting and facilitating chronic allergic contact dermatitis. They found that both skin cells and immune cells secreted OPN in allergic contact dermatitis lesions. OPN was strongly induced in antigen-specific immune cells in a murine model of chronic contact hypersensitivity, and OPN-deficient mice had a less severe chronic contact hypersensitivity response. As anti-OPN antibody treatment partially suppressed the symptoms of chronic contact hypersensitivity, OPN may serve as a new therapeutic target for allergic contact dermatitis.

Dr. Weiss's group suggests that "[their] data support a model in which OPN has an important function for [immune]-mediated skin inflammation, which may open the perspective to use anti-OPN antibody preparations for the treatment of therapy refractory [immune] cell-mediated skin disease."

Seier AM, Renkl AC, Schulz G, Uebele T, Sindrilaru A, Iben S, Liaw L, Kon S, Uede T Weiss JM: Antigen-Specific Induction of Osteopontin Contributes to the Chronification of Allergic Contact Dermatitis. Am J Pathol 2010, 176: 246-258

Weakened Plasmodium Generates Protective Immunity

Dr. Andrea Crisanti and colleagues have found that weakened Plasmodium elicits a protective immune response. They report their data in the January 2010 issue of the American Journal Pathology.

Malaria is a mosquito-borne disease that each year affects from 300-500 million people. Malaria is caused by infection with Plasmodium parasites, which go through a number of life cycle changes inside the host, increasing the challenges of malarial vaccine development.

Plasmepsin 4 is a digestive enzyme that is critical for Plasmodium growth and survival within the host red blood cells. Spaccapelo et al therefore examined Plasmodium parasites that lacked plasmepsin 4 expression for deficiencies in parasite growth and virulence. Although there was only a modest effect of plasmepsin 4 deficiency on Plasmodium growth and development within red blood cells, plasmepsin 4-null parasites were significantly less virulent than their wild-type counterparts. Infection with plasmepsin 4-deficient parasites, in contrast to infection with wild-type Plasmodium, did not induce cerebral complications. Furthermore, plasmepsin 4-null Plasmodium induced strong protective immune responses against secondary immunization with wild-type Plasmodium. Virulence-attenuated Plasmodium may therefore provide a model for assessing genetically-attenuated malarial vaccine candidates.

Dr. Crisanti and colleagues conclude that "it is possible, by engineered inactivation of parasite proteins, to generate attenuated blood stage parasites that are capable of inducing protective immunity against blood-stage infection. Such parasites should be powerful tools in elucidating parasite-derived factors that cause severe disease and should provide additional insight into factors that are required to induce protective immunity."

Spaccapelo R, Janse CJ, Caterbi S, Franke-Fayard B, Bonilla JA, Syphard LM, Di Cristina M, Dottorini T, Savarino A, Cassone A, Bistoni F, Waters AP, Dame JB, Crisanti A: Plasmepsin 4-Deficient Plasmodium berghei Are Virulence-Attenuated and Induce Protective Immunity against Experimental Malaria. Am J Pathol 2010, 176: 205-217

Inflammatory Mediator Regulates Diarrhea in Inflammatory Bowel Disease

Researchers led by Dr. Terrence A. Barrett of Northwestern University Medical School in Chicago. Illinois have discovered that activation of NK-κB, an inflammatory mediator, results in diarrhea in inflammatory bowel disease (IBD). These results are presented in the January 2010 issue of the American Journal of Pathology.

IBD, which affects approximately 1 in 500 people in the United States, describes a group of diseases, including Crohn's disease and ulcerative colitis, with inflammation in the intestinal tract. Patients with IBD experience diverse symptoms, including abdominal pain, vomiting, diarrhea, bloody stools, and weight loss.

Immune responses contribute to mucosal permeability, and hence diarrhea, in IBD; however, the mechanisms that govern this response are not completely understood. Tang et al therefore examined the role of NK-κB, an inflammatory mediator, in IBD-induced diarrhea. Following immune activation, blocking NK-κB expression in the cells lining the intestinal tract inhibited diarrhea and prevented protein changes in these cells, resulting in decreased leakiness between the cells. These findings suggest that immune cell-mediated activation of NK-κB in IBD promotes the movement of fluid into the bowel lumen, resulting in diarrhea.

Tang et al suggest that "NK-κB activation opens paracellular spaces and promotes movement of fluid into bowel lumen. Importantly, changes in permeability were associated with a net movement of water and solute into the bowel lumen. These data not only correlated with clinical signs of diarrhea but also help explain the initial fluid accumulation observed in previous studies."

Tang Y, Clayburgh DR, Mittal N, Goretsky T, Dirisina R, Zhang Z, Kron M, Ivancic D, Katzman RB, Grimm G, Lee G, Fryer J, Nusrat A, Turner JR, Barrett TA: Epithelial NK-κB enhances transmucosal fluid movement by altering tight junction protein composition after T cell activation. Am J Pathol 2010, 176: 158-167


Contact: Dr. Angela Colmone
American Journal of Pathology

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