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Research Article

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Álvaro O. Ardiles, Cheril C. Tapia-Rojas, Madhuchhanda Mandal, Frédéric Alexandre, Alfredo Kirkwood, Nibaldo C. Inestrosa, and Adrian G. Palacios
PNAS first published August 6, 2012; https://doi.org/10.1073/pnas.1201209109
Álvaro O. Ardiles
aCentro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, 2360102 Valparaíso, Chile;
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Cheril C. Tapia-Rojas
bCentro de Envejecimiento y Regeneración, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331010 Santiago, Chile;
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Madhuchhanda Mandal
cMind/Brain Institute and Department of Neurosciences, Johns Hopkins University, Baltimore, MD 21218; and
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Frédéric Alexandre
dInstitut des Maladies Neurodégénératives, Department Mnemosyne, Centre de Recherche Inria Bordeaux, F-33076 Bordeaux, France
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Alfredo Kirkwood
cMind/Brain Institute and Department of Neurosciences, Johns Hopkins University, Baltimore, MD 21218; and
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  • For correspondence: kirkwood@jhu.edu adrian.palacios@uv.cl
Nibaldo C. Inestrosa
bCentro de Envejecimiento y Regeneración, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331010 Santiago, Chile;
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Adrian G. Palacios
aCentro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, 2360102 Valparaíso, Chile;
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  • For correspondence: kirkwood@jhu.edu adrian.palacios@uv.cl
  1. Edited by Robert C. Malenka, Stanford University School of Medicine, Stanford, CA, and approved July 6, 2012 (received for review January 23, 2012)

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Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated.

  • memory dysfunction
  • neural plasticity
  • aging
  • T-maze
  • hippocampus

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: kirkwood{at}jhu.edu or adrian.palacios{at}uv.cl.
  • Author contributions: A.O.A., C.C.T.-R., A.K., N.C.I., and A.G.P. designed research; A.O.A., C.C.T.-R., and M.M. performed research; A.K., N.C.I., and A.G.P. contributed new reagents/analytic tools; A.O.A., C.C.T.-R., F.A., A.K., N.C.I., and A.G.P. analyzed data; and A.O.A., A.K., and A.G.P. wrote the paper.

  • The authors declare no conflict of interest.

  • *Ponce A, Cerpa W, Inestrosa N, Palacios AG, Aging and spatial memory in the rodent Octodon degus. Annual Meeting of the Chilean Neuroscience Society, September 27, 2006, Curico, Chile.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1201209109/-/DCSupplemental.

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Memory loss in a rodent natural model of AD
Álvaro O. Ardiles, Cheril C. Tapia-Rojas, Madhuchhanda Mandal, Frédéric Alexandre, Alfredo Kirkwood, Nibaldo C. Inestrosa, Adrian G. Palacios
Proceedings of the National Academy of Sciences Aug 2012, 201201209; DOI: 10.1073/pnas.1201209109

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Memory loss in a rodent natural model of AD
Álvaro O. Ardiles, Cheril C. Tapia-Rojas, Madhuchhanda Mandal, Frédéric Alexandre, Alfredo Kirkwood, Nibaldo C. Inestrosa, Adrian G. Palacios
Proceedings of the National Academy of Sciences Aug 2012, 201201209; DOI: 10.1073/pnas.1201209109
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Proceedings of the National Academy of Sciences: 118 (9)
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