ACCUMULATION OF AMYLOID PRECURSOR PROTEIN-LIKE IMMUNOREACTIVITY IN RAT-BRAIN IN RESPONSE TO THIAMINE-DEFICIENCY

Thiamine deficiency (TD) is a classical model of impaired cerebral oxi dation. As in Alzheimer's disease (AD), TD is characterized by selecti ve neuronal loss, decreased activities of thiamine pyrophosphate-depen dent enzymes, cholinergic deficits and memory loss. Amyloid beta-prote in (A beta), a similar to 4 kDa fragment of the beta-amyloid precursor protein (APP), accumulates in the brains of patients with AD or Down' s syndrome. In the current study, we examined APP and A beta immunorea ctivity in the brains of thiamine-deficient rats. Animals received thi amine-deficient diet ad libitum and daily injections of the thiamine a ntagonist, pyrithiamine. Immunocytochemical staining and immunoblottin g utilized a rabbit polyclonal antiserum against human APP(645-694) (n umbering according to APP(695) isoform). Three, 6 and 9 days of TD did not appear to damage any brain region nor change APP-like immunoreact ivity. However, 13 days of TD led to pathological lesions mainly in th e thalamus, mammillary body, inferior colliculus and some periventricu lar areas. While immunocytochemistry and thioflavine S histochemistry failed to show fibrillar beta-amyloid, APP-like immunoreactivity accum ulated in aggregates of swollen, abnormal neurites and perikarya along the periphery of the infarct-like lesion in the thalamus and medial g eniculate nucleus. Immunoblotting of the thalamic region around the le sion revealed increased APP-like holoprotein immunoreactivity. APP-lik e immunoreactive neurites were scattered in the mammillary body and me dial vestibular nuclei where the lesion did not resemble infarcts. In the inferior colliculus, increased perikaryal APP-like immunostaining occurred in neurons surrounding necrotic areas. Regions without appare nt pathological lesions showed no alteration in APP-like immunoreactiv ity. Thus, the oxidative insult associated with cell loss, hemorrhage and infarct-like lesions during TD leads to altered APP metabolism. Th is is the first report to show a relationship between changes in APP e xpression, oxidative metabolism and selective cell damage caused by nu tritional/cofactor deficiency. This model appears useful in defining t he role of APP in the reponse to central nervous system injury, and ma y also be relevant to the pathophysiology of Wernicke-Korsakoff syndro me and AD.