Disturbances of the blood-brain barrier without expression of amyloid precursor protein-containing neuritic clusters or neuronal loss during late stages of thiamine deficiency in guinea pigs

Generalized oxidative deficits associated with experimental thiamine deficiency (TD) lead to selective neurodegeneration, In mouse brain, TD produces region-specific breach of the blood-brain barrier (BBB), neuronal loss and an accumulation of amyloid precursor protein (APP) in abnormal neurites, The APP-laden abnormal neurites within the damaged areas of mouse brain aggregate into neuritic clusters which strikingly resemble the neuritic component of Alzheimer amyloid plaques, However, amyloid beta-peptide (A beta) immunoreactivity has not been demonstrated in these neuritic clusters, possibly because the A beta region of APP in mice contains three amino acid substitutions as compared with the amino acid sequence of human A beta. In contrast, the guinea pig nucleic acid sequence is more related to the human sequence and the A beta region is identical in sequence to that of human APP, Thus, the current studies tested whether the presence of an authentic A beta fragment of APP (i.e., identical to that of man) might make guinea pigs more vulnerable to the development of A beta-containing neuritic clusters following TD, During late stages of TD, BBB abnormalities, manifested by immunoglobulin G (IgG) extravasation and increased NADPH diaphorase reactivity in microvessels, occurred in brain areas known to be damaged by TD in mice, However, despite the prolonged thiamine deprivation and the advanced neurological symptoms of guinea pigs, no significant neuronal loss or altered APP/A beta immunostaining occurred in any brain region, Microglial activation, another early marker of damage in mice, was not evident in thiamine-deficient guinea pig brain, Ferritin immunoreactivity and iron deposition in oligodendrocytes within areas of BBB abnormalities were either slightly enhanced or unchanged as compared to controls, This is the first report of brain abnormalities in the guinea pig model of dietary and pyrithiamine-induced TD, The results demonstrate species differences in the response to TD-induced damage, and further support the role of BBB and nitric oxide in the initial events in TD pathology.