Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathological changes, including the deposition of amyloid-beta (Aβ) peptide. Aged monkeys have proven to be invaluable in the study of AD, as their brains naturally develop amyloid plaques similar to those in AD brains. However, spontaneous development of AD-like pathologies in aged monkeys is time-consuming, often taking several years. Here, we created an experimentally induced AD model in middle-aged (16-17 years) rhesus monkeys by intracranial injection of Aβ42 and thiorphan, an inhibitor of neprilysin that is responsible for Aβ clearance. The working memory capacity of the monkeys in a delayed-response task was little affected following the delivery of Aβ42 and thiorphan. However, the administration of Aβ42 and thiorphan resulted in a significant intracellular accumulation of Aβ in the neurons of the basal ganglia, the cortex, and the hippocampus, accompanied by neuronal atrophy and loss. Moreover, immunohistochemistry revealed a degeneration of choline acetyltransferase-positive cholinergic neurons and an increase of glial fibrillary acidic protein-positive astrocytes. In conclusion, our data demonstrate a primate model of AD generated by combined infusion of Aβ42 and thiorphan, which duplicates a subset of neuropathological changes in AD brains, thereby having implications in the elucidation of this disease.
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Berlau DJ, Kahle-Wrobleski K, Head E, Goodus M, Kim R, Kawas C (2007) Dissociation of neuropathologic findings and cognition: case report of an apolipoprotein E epsilon2/epsilon2 genotype. Arch Neurol 64:1193–1196
Berlau DJ, Corrada MM, Head E, Kawas CH (2009) APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology 72:829–834
Bons N, Rieger F, Prudhomme D, Fisher A, Krause KH (2006) Microcebus murinus: a useful primate model for human cerebral aging and Alzheimer’s disease? Genes Brain Behav 5:120–130
Brahmachari S, Fung YK, Pahan K (2006) Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. J Neurosci 26:4930–4939
Carter J, Lippa CF (2001) Beta-amyloid, neuronal death and Alzheimer’s disease. Curr Mol Med 1:733–737
Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204
DeKosky ST, Harbaugh RE, Schmitt FA, Bakay RA, Chui HC, Knopman DS, Reeder TM, Shetter AG, Senter HJ, Markesbery WR (1992) Cortical biopsy in Alzheimer’s disease: diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Intraventricular Bethanecol Study Group. Ann Neurol 32:625–632
Fuller AD, Van Eldik LJ (2008) MFG-E8 regulates microglial phagocytosis of apoptotic neurons. J Neuroimmune Pharmacol 3:246–256
Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yankner BA (1998) Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat Med 4:827–831
Hanna A, Horne P, Yager D, Eckman C, Eckman E, Janus C (2009) Amyloid beta and impairment in multiple memory systems in older transgenic APP TgCRND8 mice. Genes Brain Behav 8:676–84
Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356
Ichinohe N, Hayashi M, Wakabayashi K, Rockland KS (2009) Distribution and progression of amyloid-beta deposits in the amygdala of the aged macaque monkey, and parallels with zinc distribution. Neuroscience 159:1374–1383
Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6:143–150
Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, Gerard C, Hama E, Lee HJ, Saido TC (2001) Metabolic regulation of brain Abeta by neprilysin. Science 292:1550–1552
King DL, Arendash GW, Crawford F, Sterk T, Menendez J, Mullan MJ (1999) Progressive and gender-dependent cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer’s disease. Behav Brain Res 103:145–162
Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, Frosch MP, Selkoe DJ (2003) Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40:1087–1093
Liu D, Xu Y, Feng Y, Liu H, Shen X, Chen K, Ma J, Jiang H (2006) Inhibitor discovery targeting the intermediate structure of beta-amyloid peptide on the conformational transition pathway: implications in the aggregation mechanism of beta-amyloid peptide. Biochemistry 45:10963–10972
Marr RA, Rockenstein E, Mukherjee A, Kindy MS, Hersh LB, Gage FH, Verma IM, Masliah E (2003) Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci 23:1992–1996
Marr RA, Guan H, Rockenstein E, Kindy M, Gage FH, Verma I, Masliah E, Hersh LB (2004) Neprilysin regulates amyloid Beta peptide levels. J Mol Neurosci 22:5–11
McKee AC, Kowall NW, Schumacher JS, Beal MF (1998) The neurotoxicity of amyloid beta protein in aged primates. Amyloid 5:1–9
Pallas M, Camins A, Smith MA, Perry G, Lee HG, Casadesus G (2008) From aging to Alzheimer’s disease: unveiling “the switch” with the senescence-accelerated mouse model (SAMP8). J Alzheimers Dis 15:615–624
Peri F, Nüsslein-Volhard C (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133:916–927
Podlisny MB, Tolan DR, Selkoe DJ (1991) Homology of the amyloid beta protein precursor in monkey and human supports a primate model for beta amyloidosis in Alzheimer’s disease. Am J Pathol 138:1423–1435
Prohovnik I, Perl DP, Davis KL, Libow L, Lesser G, Haroutunian V (2006) Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease. Neurology 66:49–55
Roques BP, Fournié-Zaluski MC, Soroca E, Lecomte JM, Malfroy B, Llorens C, Schwartz JC (1980) The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice. Nature 288:286–288
Saido TC, Iwata N (2006) Metabolism of amyloid beta peptide and pathogenesis of Alzheimer’s disease. Towards presymptomatic diagnosis, prevention and therapy. Neurosci Res 54:235–253
Sani S, Traul D, Klink A, Niaraki N, Gonzalo-Ruiz A, Wu CK, Geula C (2003) Distribution, progression and chemical composition of cortical amyloid-beta deposits in aged rhesus monkeys: similarities to the human. Acta Neuropathol 105:145–156
Schlachetzki JC, Hüll M (2009) Microglial activation in Alzheimer’s disease. Curr Alzheimer Res 6:554–563
Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766
Selkoe DJ, Schenk D (2003) Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 43:545–584
Suh YH, Checler F (2002) Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol Rev 54:469–525
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741
Ye JW, Cai JX, Wang LM, Tang XC (1999) Improving effects of huperzine A on spatial working memory in aged monkeys and young adult monkeys with experimental cognitive impairment. J Pharmacol Exp Ther 288:814–819
Acknowledgements
This work was supported by Science and Technology Planning Project of Guangdong Province, China (2006B36004015 and 2009B060300017) and by Natural Science Foundation of Guangdong Province, China (010086 and 06023013).
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Li, W., Wu, Y., Min, F. et al. A nonhuman primate model of Alzheimer’s disease generated by intracranial injection of amyloid-beta42 and thiorphan. Metab Brain Dis 25, 277–284 (2010). https://doi.org/10.1007/s11011-010-9207-9
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DOI: https://doi.org/10.1007/s11011-010-9207-9