Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency

Noel Y. Calingasan, Samuel E. Gandy, Harriet Baker, Kwan Fu Rex Sheu, Jonathan D. Smith, Bruce Lamb, John D. Gearhart, Joseph D. Buxbaum, Clive Harper, Dennis J. Selkoe, Donald L. Price, Sangram S. Sisodia, Gary E. Gibson

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 β- protein (Aβ1-40) and thioflavine S histochemistry failed to show evidence of a component of Aβ. 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 (ie, 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.

Original languageEnglish (US)
Pages (from-to)1063-1071
Number of pages9
JournalAmerican Journal of Pathology
Volume149
Issue number3
StatePublished - Sep 1996
Externally publishedYes

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Thiamine Deficiency
Amyloid beta-Protein Precursor
Brain
Proteins
Neurites
Amyloid Plaques
Pyrithiamine
Korsakoff Syndrome
Mammillary Bodies
Amyloidogenic Proteins
Serum Amyloid A Protein
Inferior Colliculi
Thiamine
Apolipoproteins E
Thalamus
Brain Injuries
Transgenic Mice
Immune Sera
Pathology
Diet

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency. / Calingasan, Noel Y.; Gandy, Samuel E.; Baker, Harriet; Sheu, Kwan Fu Rex; Smith, Jonathan D.; Lamb, Bruce; Gearhart, John D.; Buxbaum, Joseph D.; Harper, Clive; Selkoe, Dennis J.; Price, Donald L.; Sisodia, Sangram S.; Gibson, Gary E.

In: American Journal of Pathology, Vol. 149, No. 3, 09.1996, p. 1063-1071.

Research output: Contribution to journalArticle

Calingasan, NY, Gandy, SE, Baker, H, Sheu, KFR, Smith, JD, Lamb, B, Gearhart, JD, Buxbaum, JD, Harper, C, Selkoe, DJ, Price, DL, Sisodia, SS & Gibson, GE 1996, 'Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency', American Journal of Pathology, vol. 149, no. 3, pp. 1063-1071.
Calingasan, Noel Y. ; Gandy, Samuel E. ; Baker, Harriet ; Sheu, Kwan Fu Rex ; Smith, Jonathan D. ; Lamb, Bruce ; Gearhart, John D. ; Buxbaum, Joseph D. ; Harper, Clive ; Selkoe, Dennis J. ; Price, Donald L. ; Sisodia, Sangram S. ; Gibson, Gary E. / Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency. In: American Journal of Pathology. 1996 ; Vol. 149, No. 3. pp. 1063-1071.
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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 β- protein (Aβ1-40) and thioflavine S histochemistry failed to show evidence of a component of Aβ. 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 (ie, 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.",
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AU - Buxbaum, Joseph D.

AU - Harper, Clive

AU - Selkoe, Dennis J.

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