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 oxidation. As in Alzheimer's disease (AD), TD is characterized by selective neuronal loss, decreased activities of thiamine pyrophosphate-dependent enzymes, cholinergic deficits and memory loss. Amyloid beta-protein (A beta), a approximately 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 immunoreactivity in the brains of thiamine-deficient rats. Animals received thiamine-deficient diet ad libitum and daily injections of the thiamine antagonist, pyrithiamine. Immunocytochemical staining and immunoblotting utilized a rabbit polyclonal antiserum against human APP645-694 (numbering according to APP695 isoform). Three, 6 and 9 days of TD did not appear to damage any brain region nor change APP-like immunoreactivity. However, 13 days of TD led to pathological lesions mainly in the thalamus, mammillary body, inferior colliculus and some periventricular areas. While immunocytochemistry and thioflavine S histochemistry failed to show fibrillar beta-amyloid, APP-like immunoreactivity accumulated in aggregates of swollen, abnormal neurites and perikarya along the periphery of the infarct-like lesion in the thalamus and medial geniculate nucleus. Immunoblotting of the thalamic region around the lesion revealed increased APP-like holoprotein immunoreactivity. APP-like immunoreactive neurites were scattered in the mammillary body and medial 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 apparent pathological lesions showed no alteration in APP-like immunoreactivity. Thus, the oxidative insult associated with cell loss, hemorrhage and infarct-like lesions during TD leads to altered APP metabolism. This is the first report to show a relationship between changes in APP expression, oxidative metabolism and selective cell damage caused by nutritional/cofactor deficiency. This model appears useful in defining the role of APP in the reponse to central nervous system injury, and may also be relevant to the pathophysiology of Wernicke-Korsakoff syndrome and AD.
Calingasan
N Y
NY
Cornell University Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA.
Gandy
S E
SE
Baker
H
H
Sheu
K F
KF
Kim
K S
KS
Wisniewski
H M
HM
Gibson
G E
GE
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D004435:Eating / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013832:Thiamine Deficiency / Q000378:metabolism* / Q000473:pathology; D015431:Weight Loss / Q000187:drug effects
D016564:Amyloid beta-Protein Precursor