Subpopulation of dogs with severe brain parenchymal beta amyloidosis distinguished with cluster analysis.

A study of the brains of 30 dogs, mongrels from 6.5 to 26.5 years of age, revealed that all dogs older than 13 years of age develop amyloid-beta-positive plaques. Cluster analysis based on the age of the dogs and the numerical density of amyloid-positive plaques stained with monoclonal antibody 4G8 (17-24aa) revealed that the population of old dogs consists of two subpopulations: one with a very low (0.8/mm2 on average) and other with a high (19.2/mm2 on average) numerical density of plaques. These two groups (19.5 and 19.1 years of age, respectively) appear to emerge from the younger group (12.2 years of age on average), with moderate (2.2/mm2 on average) numerical density of 4G8-positive plaques. These data may indicate that only a portion of the mongrel population (43%) is susceptible to amyloidosis beta or that only this severely affected subpopulation was exposed to a factor or factors inducing this pathology and developed severe cortical amyloidosis that correlates with age. Dog plaques are only of the diffuse type, with nonfibrillar, thioflavin S-, and Congo red-negative amyloid in all groups distinguished by cluster analysis. Only from 10% of 4G8-positive plaques in the mildly affected group to 29% in the severely and 37% in the moderately affected group are Bielschowsky positive. In the younger, moderately affected group, 6E10 (1-17aa)-positive plaques prevail. In the two old groups with severe and weak changes, almost all 4G8-positive plaques are also 6E10-positive. Carboxy-terminal region immunocytochemistry reveals that BC42-positive plaques are numerous, whereas BC40-positive plaques are few or absent. The differences in the silver-positivity of plaques and their immunoreactivity in both the amino- and carboxy-terminal regions may reflect differences in amyloid-beta deposition and resolution. Dog parenchymal amyloidosis beta appears to be a model for the study of diffuse plaques.

The origin of amyloid in cerebral vessels of aged dogs.

Our morphometric study of 30 dogs, mongrels, from 6.5 to 26.5 years of age, shows amyloid angiopathy in cortical and leptomeningeal vessels of all dogs older than 13.2 years of age, and the increase in the numerical density of amyloid-positive vessels correlated with age. Cluster analysis distinguished the group of six dogs (25%) to be relatively less affected, a large group of 13 animals (54%) to have moderate pathology, and five dogs (21%) to have severe amyloid angiopathy. Amyloid accumulation starts in large vessels, particularly in the tunica media of large arteries. Amyloid deposition appears to be associated with smooth muscle cells. Ultrastructural studies of samples from nine dogs are in agreement with in vitro studies suggesting that smooth muscle cells are the source of soluble amyloid beta. beta-protein polymerizes in the basal lamina of the tunica media. Muscle cells in the area of amyloid-beta accumulation degenerate and die. Thioflavin-positivity of only 24% of cortical and 66% of leptomeningeal beta-protein-positive vessels suggests that thioflavin-negative deposits contain soluble, not yet fibrillized protein and/or partially degraded and depolymerized amyloid.