Amyloid-ß immunotherapy reduces amyloid plaques and astroglial reaction in aged domestic dogs.

BACKGROUND: Alzheimer's disease (AD) is characterized by the dynamic accumulation of extracellular amyloid deposits from the interplay between amyloid-ß (Aß) plaques, reactive astrocytes and activated microglia. Several immunotherapies against Aß have been shown to reduce amyloid neuropathology. However, the role of the associated glia in the recovery process requires clarification. Previously, we described the safety and effectiveness in aged domestic canine with cognitive dysfunction syndrome of a new active vaccine candidate for the treatment of AD in humans. OBJECTIVE: The aim of this article is to gain a better understanding of how immunotherapy modifies the amyloid burden and its effects on astroglial and microglial reactivity in immunized dogs. METHODS: In order to achieve this, we compared and quantified amyloid plaques and astroglial and microglial reactions in the frontal cortex of unimmunized and immunized aged domestic dogs. RESULTS: We found amyloid plaques from immunized dogs to be smaller and more compact than those from unimmunized dogs. In these new plaques, the associated astrocytes were closer and less immunoreactive to the ß subunit of S100 protein (S100B). We also found no modification in the microglial reaction associated with immunization. CONCLUSION: The anti-Aß immunotherapy developed in our laboratory modifies the equilibrium between soluble and insoluble Aß in aged dogs in close correlation with S100B-negative astrocytosis and microglial reaction.

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. METHODS: Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNγ)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35₋55). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration. RESULTS: Diazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord. CONCLUSION: Taken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.

Alzheimer's disease modifies progenitor cell expression of monoamine oxidase B in the subventricular zone.

In the adult brain, progenitor cells remaining in the subventricular zone (SVZ) are frequently identified as glial fibrillary acidic protein (GFAP)-positive cells that retain attributes reminiscent of radial glia. Because the very high expression of monoamine oxidase B (MAO-B) in the subventricular area has been related to epithelial and astroglial expression, we sought to ascertain whether it was also expressed by progenitor cells of human control and Alzheimer's disease (AD) patients. In the SVZ, epithelial cells and astrocyte-like cells presented rich MAO-B activity and immunolabeling. Nestin-positive cells were found in the same area, showing a radial glia-like morphology. When coimmunostaining and confocal microscopy were performed, most nestin-positive cells showed MAO-B activity and labeling. The increased progenitor activity in SVZ proposed for AD patients was confirmed by the positive correlation between the SVZ nestin/MAO-B ratio and the progression of the disease. Nestin/GFAP-positive cells, devoid of MAO-B, can represent a distinct subpopulation of an earlier phase of maturation. This would indicate that MAO-B expression takes place in a further step of nestin/GFAP-positive cell differentiation. In the early AD stages, the discrete MAO-B reduction, different from the severe GFAP decrease, would reflect the capacity of this population of MAO-B-positive progenitor cells to adapt to the neurodegenerative process.

Rapid improvement of canine cognitive dysfunction with immunotherapy designed for Alzheimer's disease.

Immunotherapy against amyloid-ß(Aß) may improve rodent cognitive function by reducing amyloid neuropathology and is being validated in clinical trials with positive preliminary results. However, for a complete understanding of the direct and long-term immunization responses in the aged patient, and also to avoid significant side effects, several key aspects remain to be clarified. Thus, to investigate brain Aß clearance and Th2 responses in the elderly, and the reverse inflammatory events not found in the immunized rodent, better Alzheimer's disease (AD) models are required. In the aged familiar canine with a Cognitive Dysfunction Syndrome (CDS) we describe the rapid effectiveness and the full safety profile of a new active vaccine candidate for human AD prevention and treatment. In these aged animals, besidesa weak immune system, the antibody response activated a coordinated central and peripheral Aß clearance, that rapidly improved their cognitive function in absence of any side effects. Our results also confirm the interest to use familiar dogs to develop innovative and reliable therapies for AD.

Dogs with cognitive dysfunction syndrome: a natural model of Alzheimer's disease.

In the search for appropriate models for Alzheimer's disease (AD) involving animals other than rodents, several laboratories are working with animals that naturally develop cognitive dysfunction. Among the animals tested, dogs are quite unique in helping to elucidate the cascade of events that take place in brain amyloid-beta (Aß)deposition aging, and cognitive deficit. Recent innovative research has validated human methods and tools for the analysis of canine neuropathology and has allowed the development of two different approaches to investigate dogs as natural models of AD. The first approach relates AD-like neuropathy with the decline in memory and learning ability in aged housed dogs in a highly controlled laboratory environment. The second approach involves research in family-owned animals with cognitive dysfunction syndrome. In this review, we compare the strengths and limitations of housed and family-owned canine models, and appraise their usefulness for deciphering the early mechanisms of AD and developing innovative therapies.