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 (Aβ) 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.KEYWORDS: aging, Amyloid-beta, animal model, canine cognitive dysfunction syndrome, family dog, therapies. 6 Why a canine model of AD?For years, the search for appropriate animal models for Alzheimer's disease (AD) has focused on a variety of manipulations to reproduce the disease in various species, such as yeast, Drosophyla melanogaster, Caenorabditis elegans, rodents, and rabbits, with a particular interest in obtaining knockout and transgenic animals (for a review, see [1]research is currently performed in the mouse because its brain structure is somewhat similar to that of humans, and it is amenable to highly sophisticated genetic engineering. Because age-related cognitive decline is a common feature of most mammals, other laboratories have focused on the few species that naturally develop cognitive dysfunction with various Alzheimer-like characteristics. These animals include the monkey, polar bear, cat and dog [2][3][4][5]. Canine models are currently considered a useful intermediate between genetically modified mouse models and humans [6,7]. Although many of the transgenic AD models have provided insights into the molecular mechanisms of the pathology, none of them encompass all the cognitive deficits observed in AD (see Table 1). One of the first transgenic mouse AD models was the amyloid precursor protein transgenic mouse, PDAPP mouse, which develops age-dependent amyloid beta accumulation and deposition in both diffuse and fibrillar neuritic plaques in the hippocampus, cerebral cortex, and corpus callosum [8]. Other models with AD-like pathology are apolipoprotein E (ApoE) or Tau transgenic mice, and also mice in which other genes have been modified. In more sophisticated approaches, important information has been gained from crossing PDAPP and ApoE models and with mice lacking or over-expressing genes for beta-secretase, alpha-secretase, or the insulin-degrading enzyme [9,10].All these models have provided valuable information on AD pathology and on the poss...

ABSTRACT:Immunotherapy against amyloid-beta (Aβ) 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 Aβ 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, besides a weak immune system, the antibody response activated a coordinated central and peripheral Aβ 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.

Background: Alzheimer's disease (AD) is characterized by the dynamic accumulation of extracellular amyloid deposits from the interplay between amyloid-β (Aβ) plaques, reactive astrocytes and activated microglia. Several immunotherapies against Aβ 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 β subunit of S100 protein (S100B). We also found no modification in the microglial reaction associated with immunization. Conclusion: The anti-Aβ immunotherapy developed in our laboratory modifies the equilibrium between soluble and insoluble Aβ in aged dogs in close correlation with S100B-negative astrocytosis and microglial reaction.