TY - JOUR
T1 - Accumulation of amyloid precursor protein-like immunoreactivity in rat brain in response to thiamine deficiency
AU - Calingasan, Noel Y.
AU - Gandy, Samuel E.
AU - Baker, Harriet
AU - Sheu, Kwan Fu Rex
AU - Kim, Kwang Soo
AU - Wisniewski, Henryk M.
AU - Gibson, Gary E.
N1 - Funding Information:
This research work was supported by NIH grants MH-48325 (to Dr. Gary E. Gibson) and AG-11508 (to Dr. Samuel E. Gandy). The authors thank Dr. Lorraine DeGiorgio for her help in neurofilament immunocytochemistry, Charles Carver for his expertise in scanning densitometry and preparing photographs of the immunoblots, and Allison Wong for her help in preparing the sections.
PY - 1995/4/17
Y1 - 1995/4/17
N2 - 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 β-protein (Aβ), a ∼4 kDa fragment of the β-amyloid precursor protein (APP), accumulates in the brains of patients with AD or Down's syndrome. In the current study, we examined APP and Aβ immunoreactivity in the brains of thiamine-deficient rats. Animals received thiamine-deficient diet and 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 β-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 response to central nervous system injury, and may also be relevant to the pathophysiology of Wernicke-Korsakoff syndrome and AD.
AB - 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 β-protein (Aβ), a ∼4 kDa fragment of the β-amyloid precursor protein (APP), accumulates in the brains of patients with AD or Down's syndrome. In the current study, we examined APP and Aβ immunoreactivity in the brains of thiamine-deficient rats. Animals received thiamine-deficient diet and 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 β-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 response to central nervous system injury, and may also be relevant to the pathophysiology of Wernicke-Korsakoff syndrome and AD.
KW - Alzheimer's disease
KW - Immunocytochemistry
KW - Neurodegeneration
KW - Thiamine deficiency
KW - Wernicke-Korsakoff syndrome
KW - β-amyloid precursor protein
UR - https://www.scopus.com/pages/publications/0028986273
U2 - 10.1016/0006-8993(95)00136-E
DO - 10.1016/0006-8993(95)00136-E
M3 - Article
C2 - 7606469
AN - SCOPUS:0028986273
SN - 0006-8993
VL - 677
SP - 50
EP - 60
JO - Brain Research
JF - Brain Research
IS - 1
ER -