Mild Microglial Responses in the Cortex and Perivascular Macrophage Infiltration in Subcortical White Matter in Dogs with Age-Related Dementia Modelling Prodromal Alzheimer's Disease.

BACKGROUND: Microglia contribute to Alzheimer's disease (AD) pathogenesis by clearing amyloid-ß (Aß) and driving neuroinflammation. Domestic dogs with age-related dementia (canine cognitive dysfunction (CCD)) develop cerebral amyloidosis like humans developing AD, and studying such dogs can provide novel information about microglial response in prodromal AD. OBJECTIVE: The aim was to investigate the microglial response in the cortical grey and the subcortical white matter in dogs with CCD versus age-matched cognitively normal dogs. METHODS: Brains from aged dogs with CCD and age-matched controls without dementia were studied. Cases were defined by dementia rating score. Brain sections were stained for Aß, thioflavin S, hyperphosphorylated tau, and the microglial-macrophage ionized calcium binding adaptor molecule 1 (Iba1). Results were correlated to dementia rating score and tissue levels of Aß. RESULTS: Microglial numbers were higher in the Aß plaque-loaded deep cortical layers in CCD versus control dogs, while the coverage by microglial processes were comparable. Aß plaques were of the diffuse type and without microglial aggregation. However, a correlation was found between the %Iba1 area and insoluble Aß 42 and N-terminal pyroglutamate modified Aß(N3pE)-42. The %Iba1 area was higher in white matter, showing phosphorylation of S396 tau, versus grey matter. Perivascular macrophage infiltrates were abundant in the white matter particularly in CDD dogs. CONCLUSION: The results from this study of the microglial-macrophage response in dogs with CCD are suggestive of relatively mild microglial responses in the Aß plaque-loaded deep cortical layers and perivascular macrophage infiltrates in the subcortical white matter, in prodromal AD.

Dogs with Cognitive Dysfunction as a Spontaneous Model for Early Alzheimer's Disease: A Translational Study of Neuropathological and Inflammatory Markers.

Aged companion dogs with canine cognitive dysfunction (CCD) spontaneously develop varying degrees of progressive cognitive decline and particular neuropathological features correspondent to the changes associated with Alzheimer's disease (AD) in humans. The aim of the present study was to characterize certain aspects of neuropathology and inflammatory markers related to aging and CCD in dogs in comparison with human AD. Fifteen brains from aged dogs with normal cognitive function, mild cognitive impairment, or CCD were investigated and compared with two control brains from young dogs and brain sections from human AD subjects. The neuropathological investigations included evaluation of amyloid-ß (Aß) plaque deposition (N-terminally truncated and pyroglutamyl-modified Aß included), tau pathology, and inflammatory markers in prefrontal cortex. Cortical Aß deposition was found to be only of the diffuse subtype as no dense-core or neuritic plaques were found. The Aß deposition followed a progressive pattern in four maturation stages. Accumulation of the Aß peptide was also observed in the vessel walls. Both immunohistochemically and biochemically measured levels of Aß pathology in prefrontal cortex showed a consistent positive correlation to age but not to cognitive deficit severity. No evidence of neurofibrillary tau pathology was found. The level of pro-inflammatory cytokines was generally low and showed no significant association to cognitive status. The findings of the present study support the senescent dog with spontaneous cognitive dysfunction as a valuable non-transgenic model for further investigations of the molecular events involved in the neurodegenerative processes associated with aging and early stage AD, especially the Aß-related pathology.

Decreased plasma concentration of nitric oxide metabolites in dogs with untreated mitral regurgitation.

Endothelium-dependent (nitric oxide [NO]-mediated) vasodilation is impaired in humans with heart failure. This dysfunction is an important therapeutic target. The plasma concentration of the NO metabolites nitrate and nitrite (collectively referred to as NOx) is a measure of whole-body NO production, provided that the dietary intake of the ions is low. Fifty clinically healthy dogs older than I year (median 5.0 years; interquartile interval 2.6-8.2 years) were studied, including 9 controls of various breeds, 23 Cavalier King Charles Spaniels (CKCSs) with no or minimal mitral regurgitation (MR), 9 CKCSs with mild MR (regurgitant jet occupying 15-50% of the left atrial area), and 9 CKCS with moderate to severe MR (jet >50%) due to myxomatous valve disease. None of the dogs received medication. The dogs were given NOx-free water and a diet with a low concentration of NOx for 96 hours before blood sampling. Multiple linear regression analysis revealed that dog group, but not gender, age, serum creatinine concentration, and platelet count, was associated with NOx concentrations. Control dogs had the same NOx concentration (median 20.0 microM; interquartile interval 15.1-25.5 microM) as CKCSs without MR (median 18.7 microM; interquartile interval 15.5-25.9 microM). Compared to CKCSs without MR, the NOx concentration was lower in CKCSs with mild (median 12.9 microM; interquartile interval 11.0-13.5 microM; P = .04) and moderate to severe (median 11.2 microM; interquartile interval 6.9-17.1 microM; P = .02) MR. In conclusion, CKCSs with mild to severe, clinically silent MR have decreased plasma NOx concentrations, suggesting that endothelial dysfunction develops early in the course of developing MR in dogs.