title: Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency.
abstract: Experimental thiamine deficiency (TD) is a classical model of a nutritional deficit associated with a generalized impairment of oxidative metabolism and selective cell loss in the brain. In rats, TD-induced cell degeneration is accompanied by an accumulation of amyloid precursor protein (APP)/amyloid precursor-like protein 2 (APLP2) immunoreactivity in abnormal neurites and perikarya along the periphery of, or scattered within, the lesion. Prompted by these data and our previous findings of a genetic variation in the development of TD symptoms, we extended our studies to mice. C57BL/6, ApoE knockout, and APP YAC transgenic mice received thiamine-deficient diet and pyrithiamine injections. Unlike rats, APP/APLP2-immunoreactive neurites in all strains of mice were sparsely scattered within damaged areas and did not delimit the thalamic lesion. In addition, abnormal clusters of intensely immunoreactive neurites occurred only in areas of damage including the thalamus, mammillary body, and inferior colliculus. The clusters appeared as either irregular clumps or round or oval rosettes that strikingly resembled the neuritic component of Alzheimer amyloid plaques. However, immunostaining using various antisera to synthetic amyloid beta-protein (A beta 1-40) and thioflavine S histochemistry failed to show evidence of a component of A beta Neither APP/APLP2-immunoreactive clusters nor amyloid plaques were observed in the brain from patients with Wernicke-Korsakoff syndrome, the clinical manifestation of TD in man. Our results demonstrate species (i.e., genetic) differences in the response to TD-induced damage and support a role for APP and APLP2 in the response to brain injury. This is the first report that chronic oxidative deficits can lead to this novel pathology.
authors.affiliation: Cornell University Medical College, Burke Medical Research Institute, White Plains, New York 10605, USA.
authors.forename: N Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: S E
authors.initials: SE
authors.lastname: Gandy
authors.forename: H
authors.initials: H
authors.lastname: Baker
authors.forename: K F
authors.initials: KF
authors.lastname: Sheu
authors.forename: J D
authors.initials: JD
authors.lastname: Smith
authors.forename: B T
authors.initials: BT
authors.lastname: Lamb
authors.forename: J D
authors.initials: JD
authors.lastname: Gearhart
authors.forename: J D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: C
authors.initials: C
authors.lastname: Harper
authors.forename: D J
authors.initials: DJ
authors.lastname: Selkoe
authors.forename: D L
authors.initials: DL
authors.lastname: Price
authors.forename: S S
authors.initials: SS
authors.lastname: Sisodia
authors.forename: G E
authors.initials: GE
authors.lastname: Gibson
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D013832:Thiamine Deficiency / Q000503:physiopathology*; D014899:Wernicke Encephalopathy / Q000276:immunology / Q000473:pathology
chemical_list: C489697:APLP1 protein, human; C084104:APLP2 protein, human; D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; C492952:Aplp2 protein, mouse; D009419:Nerve Tissue Proteins