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Amyloidosis increase is not attenuated by long-term calorie restriction or related to neuron density in the prefrontal cortex of extremely aged rhesus macaques

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Abstract

As human lifespan increases and the population ages, diseases of aging such as Alzheimer’s disease (AD) are a major cause for concern. Although calorie restriction (CR) as an intervention has been shown to increase healthspan in many species, few studies have examined the effects of CR on brain aging in primates. Using postmortem tissue from a cohort of extremely aged rhesus monkeys (22–44 years old, average age 31.8 years) from a longitudinal CR study, we measured immunohistochemically labeled amyloid beta plaques in Brodmann areas 32 and 46 of the prefrontal cortex, areas that play key roles in cognitive processing, are sensitive to aging and, in humans, are also susceptible to AD pathogenesis. We also evaluated these areas for cortical neuron loss, which has not been observed in younger cohorts of aged monkeys. We found a significant increase in plaque density with age, but this was unaffected by diet. Moreover, there was no change in neuron density with age or treatment. These data suggest that even in the oldest-old rhesus macaques, amyloid beta plaques do not lead to overt neuron loss. Hence, the rhesus macaque serves as a pragmatic animal model for normative human aging but is not a complete model of the neurodegeneration of AD. This model of aging may instead prove most useful for determining how even the oldest monkeys are protected from AD, and this information may therefore yield valuable information for clinical AD treatments.

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Abbreviations

Aβ:

Amyloid beta

AD:

Alzheimer’s disease

APOE:

Apolipoprotein E

APP:

Amyloid precursor protein

BA 32:

Brodmann Area 32 of the cingulate cortex

BA 46:

Brodmann Area 46 of the prefrontal cortex

CDC:

Centers for Disease Control and Prevention

CR:

Calorie restriction

MCI:

Mild cognitive impairment

NeuN:

Neuronal nucleic protein

NHP:

Nonhuman primate

NIA:

National Institute on Aging

PFC:

Prefrontal cortex

ROI:

Region of interest

TBS:

7.6 pH Tris-buffered saline

US:

United States of America

References

  1. Colby SL, Ortman JM (2015) Projections of the size and composition of the U.S. population: 2014 to 2060. U.S. Census Bureau: Population Estimates and Projections. Retrieved from: https://www.census.gov/content/dam/Census/library/publications/2015/demo/p25-1143.pdf

  2. Maust D, Langa K, Solway E, Singer D, Kirch M, Kullgren J, et al. Thinking about brain health: University of Michigan National Poll on Healthy Aging; 2019. Available at: http://hdl.handle.net/2027.42/149132

  3. Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med. 2013;29:737–52. https://doi.org/10.1016/j.cger.2013.07.002.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schott JM. The neurology of ageing: what is normal? Pract Neurol. 2017;17:172–82. https://doi.org/10.1136/practneurol-2016-001566.

    Article  PubMed  Google Scholar 

  5. von Strauss E, Viitanen M, De Ronchi D, Winblad B, Fratiglioni L. Aging and the occurrence of dementia. Arch Neurol. 1999;56:587–92. https://doi.org/10.1001/archneur.56.5.587.

    Article  Google Scholar 

  6. Deb A, Thornton JD, Sambamoorthi U, Innes K. Direct and indirect cost of managing Alzheimer’s disease and related dementias in the United States. Expert Rev Pharmacoecon Outcomes Res. 2017;2:189–202. https://doi.org/10.1080/14737167.2017.1313118.

    Article  Google Scholar 

  7. Hurd MD, Martorell P, Delavande A, Mullen KJ, Langa KM. Monetary costs of dementia in the United States. N Engl J Med. 2013;368:1326–34. https://doi.org/10.1056/NEJMsa1204629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tejada-Vera B. Mortality from Alzheimer’s disease in the United States: data for 2000 and 2010. NCHS data brief. 2013;116:1–8.

    Google Scholar 

  9. Freeman SH, Kandel R, Cruz L, Rozkalne A, Newell K, Frosch MP, et al. Preservation of neuronal number despite age-related cortical brain atrophy in elderly subjects without Alzheimer disease. J Neuropathol Exp Neurol. 2008;67:1205–12.

    Article  Google Scholar 

  10. Marner L, Nyengaard JR, Tang Y, Pakkenberg B. Marked loss of myelinated nerve fibers in the human brain with age. J Comp Neurol. 2003;462:144–52. https://doi.org/10.1002/cne.10714.

    Article  PubMed  Google Scholar 

  11. Furcila D, Defelipe J, Alonso-Nanclares L. A study of amyloid-β and phosphotau in plaques and neurons in the hippocampus of Alzheimer’s disease patients. J Alzheimers Dis. 2018;64:417–35. https://doi.org/10.3233/JAD-180173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5–36. https://doi.org/10.1007/s00401-009-0532-1.

    Article  CAS  PubMed  Google Scholar 

  13. Cummings JL, Cohen S, Van Dyck CH, Brody M, Curtis C, Cho W, et al. A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018;90:E1889–97. https://doi.org/10.1212/WNL.0000000000005550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med. 2019;380:1408–20. https://doi.org/10.1056/NEJMoa1812840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Farlow M, Arnold SE, Van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 2012;8:261–71. https://doi.org/10.1016/j.jalz.2011.09.224.

    Article  CAS  PubMed  Google Scholar 

  16. Haass C, Levin J. Hat die Alzheimer-Forschung versagt? : Das Scheitern amyloidbasierter klinischer Studien [Did Alzheimer research fail entirely? : Failure of amyloid-based clinical studies]. Nervenarzt. 2019;90:884–90. https://doi.org/10.1007/s00115-019-0751-1.

    Article  PubMed  Google Scholar 

  17. Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9:1–15. https://doi.org/10.1186/s13195-017-0318-y.

    Article  CAS  Google Scholar 

  18. Kishi T, Hirooka Y, Nagayama T, Isegawa K, Katsuki M, Takesue K, et al. Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor: Tropomyosin-related kinase B in hippocampus of obesity-induced hypertensive rats. Int Heart J. 2015;56:110–5. https://doi.org/10.1536/ihj.14-168.

    Article  PubMed  Google Scholar 

  19. McCay CM, Crowell MF. Prolonging the life span. Science. 1934;39:405–14 https://www.jstor.org/stable/15813.

    Google Scholar 

  20. Parrella E, Maxim T, Maialetti F, Zhang L, Wan J, Wei M, et al. Protein restriction cycles reduce IGF-1 and phosphorylated tau, and improve behavioral performance in an Alzheimer’s disease mouse model. Aging Cell. 2013;12:257–68. https://doi.org/10.1111/acel.12049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wahl D, Coogan SCP, Solon-Biet SM, Haran JB, Raubenheimer D, Cogger VC, et al. Cognitive and behavioral evaluation of nutritional interventions in rodent models of brain aging and dementia. Clin Interv Aging. 2017;12:1419–28. https://doi.org/10.2147/CIA.S145247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gültekin F, Nazıroğlu M, Savaş HB, Çiğ B. Calorie restriction protects against apoptosis, mitochondrial oxidative stress and increased calcium signaling through inhibition of TRPV1 channel in the hippocampus and dorsal root ganglion of rats. Metab Brain Dis. 2018;33:1761–74. https://doi.org/10.1007/s11011-018-0289-0.

    Article  CAS  PubMed  Google Scholar 

  23. Hadad N, Unnikrishnan A, Jackson JA, Masser DR, Otalora L, Stanford DR, et al. Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation. Neurobiol Aging. 2018;67:53–66. https://doi.org/10.1016/j.neurobiolaging.2018.03.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kraus WE, Bhapkar M, Huffman KM, Pieper CF, Krupa Das S, Redman LM, et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7:673–83. https://doi.org/10.1016/S2213-8587(19)30151-2.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Martin CK, Bhapkar M, Pittas AG, Pieper CF, Das SK, Williamson DA, et al. Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults the CALERIE 2 randomized clinical trial. JAMA Intern Med. 2016;176:743–52. https://doi.org/10.1001/jamainternmed.2016.1189.

    Article  PubMed  PubMed Central  Google Scholar 

  26. LaFerla FM, Green KN. Animal models of Alzheimer’s disease. Cold Spring Harb Perspect Med. 2012;2:1031–85. https://doi.org/10.1016/B978-0-12-809468-6.00040-1.

    Article  Google Scholar 

  27. Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG, Laferla FM, et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer’s disease. Neurobiol Dis. 2007;26:212–20. https://doi.org/10.1016/j.nbd.2006.12.019.

    Article  CAS  PubMed  Google Scholar 

  28. Ingram DK, De Cabo R. Calorie restriction in rodents: caveats to consider. Ageing Res Rev. 2017;39:15–28. https://doi.org/10.1016/j.arr.2017.05.008.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ. Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet. 2014;5:1–23. https://doi.org/10.3389/fgene.2014.00088.

    Article  CAS  Google Scholar 

  30. Colman RJ. Non-human primates as a model for aging. Biochim Biophys Acta - Mol Basis Dis. 2018;1864:2733–41. https://doi.org/10.1016/j.bbadis.2017.07.008.

    Article  CAS  PubMed  Google Scholar 

  31. Gibbs RA, Rogers J, Katze MG, Bumgarner R, Weinstock GM, Mardis ER, et al. Evolutionary and biomedical insights from the rhesus macaque genome. Science. 2007;316:222–34. https://doi.org/10.1126/science.1139247.

    Article  CAS  PubMed  Google Scholar 

  32. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, et al. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017;8:1–12. https://doi.org/10.1038/ncomms14063.

    Article  CAS  Google Scholar 

  33. Moore TL, Killiany RJ, Herndon JG, Rosene DL, Moss MB. Executive system dysfunction occurs as early as middle-age in the rhesus monkey. Neurobiol Aging. 2006;27:1484–93. https://doi.org/10.1016/j.neurobiolaging.2005.08.004.

    Article  PubMed  Google Scholar 

  34. Nagahara AH, Bernot T, Tuszynski MH. Age-related cognitive deficits in rhesus monkeys mirror human deficits on an automated test battery. Neurobio Aging. 2010;31:1–13. https://doi.org/10.1038/jid.2014.371.

    Article  CAS  Google Scholar 

  35. Peters A, Rosene DL, Moss MB, Kemper TL, Abraham CR, Tigges J, et al. Neurobiological bases of age-related cognitive decline in the rhesus monkey. J Neuropath Exp Neuro. 1996;55:861–74. https://doi.org/10.1097/00005072-199608000-00001.

    Article  CAS  Google Scholar 

  36. Rapp P. Neuropsychological analysis of learning and memory in the aged nonhuman primate. Neurobiol Aging. 1993;14:627–9. https://doi.org/10.1016/0197-4580(93)90050-L.

    Article  CAS  PubMed  Google Scholar 

  37. Heilbroner PL, Kemper TL. The cytoarchitectonic distribution of senile plaques in three aged monkeys. Acta Neuropathol. 1990;81:60–5. https://doi.org/10.1007/BF00662638.

    Article  CAS  PubMed  Google Scholar 

  38. Uno H. The incidence of senile plaques and multiple infarction in aged macaque brain. Neurobiol Aging. 1993;14:673–4. https://doi.org/10.1016/0197-4580(93)90067-L.

    Article  CAS  PubMed  Google Scholar 

  39. Gandy S, DeMattos RB, Lemere CA, Heppner FL, Leverone J, Aguzzi A, et al. Alzheimer’s Abeta vaccination of rhesus monkeys (Macaca mulatta). Mech Ageing Dev. 2004;125:149–51. https://doi.org/10.1016/j.mad.2003.12.002.

    Article  CAS  PubMed  Google Scholar 

  40. Gearing M, Rebeck GW, Hyman BT, Tigges J, Mirra SS. Neuropathology and apolipoprotein E profile of aged chimpanzees: implications for Alzheimer disease. Proc Natl Acad Sci U S A. 1994;91:9382–6. https://doi.org/10.1073/pnas.91.20.9382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Paspalas CD, Carlyle BC, Leslie S, Preuss TM, Crimins JL, Huttner AJ, et al. The aged rhesus macaque manifests Braak stage III/IV Alzheimer’s-like pathology. Alzheimers Dement. 2018;14:680–91. https://doi.org/10.1016/j.jalz.2017.11.005.

    Article  PubMed  Google Scholar 

  42. Gazzaley AH, Thakker MM, Hof PR, Morrison JH. Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys. Neurobiol Aging. 1997;18:549–53. https://doi.org/10.1016/S0197-4580(97)00112-7.

    Article  CAS  PubMed  Google Scholar 

  43. Giannaris EL, Rosene DL. A stereological study of the numbers of neurons and glia in the primary visual cortex across the lifespan of male and female rhesus monkeys. J Comp Neurol. 2012;520:3492–508. https://doi.org/10.1002/cne.23101.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hof PR, Nimchinsky EA, Young WG, Morrison JH. Numbers of Meynert and layer IVB cells in area V1: a stereologic analysis in young and aged macaque monkeys. J Comp Neurol. 2000;420:113–26. https://doi.org/10.1002/(SICI)1096-9861(20000424)420:1<113::AID-CNE8>3.0.CO;2-N.

    Article  CAS  PubMed  Google Scholar 

  45. Keuker JIH, Luiten PGM, Fuchs E. Preservation of hippocampal neuron numbers in aged rhesus monkeys. Neurobiol Aging. 2003;24:157–65. https://doi.org/10.1016/S0197-4580(02)00062-3.

    Article  PubMed  Google Scholar 

  46. Merrill DA, Roberts JA, Tuszynski MH. Conservation of neuron number and size in entorhinal cortex layers II, III, and V/VI of aged primates. J Comp Neurol. 2000;422:396–401. https://doi.org/10.1002/1096-9861(20000703)422:3<396::AID-CNE6>3.0.CO;2-R.

    Article  CAS  PubMed  Google Scholar 

  47. Peters A, Morrison JH, Rosene DL, Hyman BT. Feature article are neurons lost from the primate cerebral cortex during normal aging? Cereb Cortex. 1998;8:295–300. https://doi.org/10.1093/cercor/8.4.295.

    Article  CAS  PubMed  Google Scholar 

  48. Roberts DE, Killiany RJ, Rosene DL. Neuron numbers in the hypothalamus of the normal aging rhesus monkey: stability across the adult lifespan and between the sexes. J Comp Neurol. 2012;520:1181–97. https://doi.org/10.1002/cne.22761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Smith DE, Rapp PR, McKay HM, Roberts JA, Tuszynski MH. Memory impairment in aged primates is associated with focal death of cortical neurons and atrophy of subcortical neurons. J Neurosci. 2004;24:4373–81. https://doi.org/10.1523/JNEUROSCI.4289-03.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bodkin NL, Alexander TM, Ortmeyer HK, Johnson E, Hansen BC. Mortality and morbidity in laboratory-maintained rhesus monkeys and effects of long-term dietary restriction. J Geron. 2003;58A:212–9.

    Article  Google Scholar 

  51. Mattison JA, Vaughan KL. An overview of nonhuman primates in aging research. Exp Gerontol. 2017;94:41–5. https://doi.org/10.1016/j.exger.2016.12.005.

    Article  PubMed  Google Scholar 

  52. Mattison JA, Black A, Huck J, Moscrip T, Handy A, Tilmont E, et al. Age-related decline in caloric intake and motivation for food in rhesus monkeys. Neurobiol Aging. 2005;26:1117–27. https://doi.org/10.1016/j.neurobiolaging.2004.09.013.

    Article  PubMed  Google Scholar 

  53. Matthews KA, Xu W, Gaglioti AH, Holt JB, Croft JB, Mack D, et al. Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015–2060) in adults aged ≥65 years. Alzheimers Dement. 2019;15:17–24. https://doi.org/10.1016/j.jalz.2018.06.3063.

    Article  PubMed  Google Scholar 

  54. Peters A, Kemper T. A review of the structural alterations in the cerebral hemispheres of the aging rhesus monkey. Neurobiol Aging. 2012;33:2357–72. https://doi.org/10.1016/j.neurobiolaging.2011.11.015.

    Article  PubMed  Google Scholar 

  55. Peters A, Leahu D, Moss MB, Mcnally KJ. The effects of aging on area 46 of the frontal cortex of the rhesus monkey. Cereb Cortex. 1994;4:621–35. https://doi.org/10.1093/cercor/4.6.621.

    Article  CAS  PubMed  Google Scholar 

  56. Primiani CT, Ryan VH, Rao JS, Cam MC, Ahn K, Modi HR, et al. Coordinated gene expression of neuroinflammatory and cell signaling markers in dorsolateral prefrontal cortex during human brain development and aging. PLoS One. 2014;9:e110972. https://doi.org/10.1371/journal.pone.0110972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yuan Y, Chen YPP, Boyd-Kirkup J, Khaitovich P, Somel M. Accelerated aging-related transcriptome changes in the female prefrontal cortex. Aging Cell. 2012;11:894–901. https://doi.org/10.1111/j.1474-9726.2012.00859.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dumas JA, Kutz AM, McDonald BC, Naylor MR, Pfaff AC, Saykin AJ, et al. Increased working memory-related brain activity in middle-aged women with cognitive complaints. Neurobiol Aging. 2013;34:1145–7. https://doi.org/10.1016/j.neurobiolaging.2012.08.013.

    Article  PubMed  Google Scholar 

  59. Gigi A, Babai R, Katzav E, Atkins S, Hendler T. Prefrontal and parietal regions are involved in naming of objects seen from unusual viewpoints. Beh Neuro. 2007;121:836–44. https://doi.org/10.1037/0735-7044.121.5.836.

    Article  Google Scholar 

  60. Pimontel MA, Kanellopoulos D, Gunning FM. Neuroanatomical abnormalities in older depressed adults with apathy: a systematic review. J Geriatr Psychiatry Neurol. 2019;33:289–303. https://doi.org/10.1177/0891988719882100.

    Article  PubMed  Google Scholar 

  61. Shamy JL, Habeck C, Hof PR, Amaral DG, Fong SG, Buonocore MH, et al. Volumetric correlates of spatiotemporal working and recognition memory impairment in aged rhesus monkeys. Cereb Cortex. 2011;21:1559–73. https://doi.org/10.1093/cercor/bhq210.

    Article  PubMed  Google Scholar 

  62. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012;489:318–21. https://doi.org/10.1038/nature11432.

    Article  CAS  PubMed  Google Scholar 

  63. Ingram DK, Cutler RG, Weindruch R, Renquist DM, Knapa JJ, April M, et al. Dietary restriction and aging: the initiation of a primate study. J Gerontol. 1990;45:B148–63. https://doi.org/10.1093/geronj/45.5.b148.

    Article  CAS  PubMed  Google Scholar 

  64. Rosene DL, Roy NJ, Davis BJ. A cryoprotection method that facilitates cutting frozen sections of whole monkey brains for histological and histochemical processing without freezing artifact. J Histochem Cytochem. 1986;34:1301–15.

    Article  CAS  Google Scholar 

  65. Estrada LI, Robinson AA, Amaral AC, Giannaris EL, Heyworth NC, Mortazavi F, Ngwenya LB, Roberts DE, Cabral HJ, Killiany RJ, Rosene DL (2017) Evaluation of long-term cryostorage of brain tissue sections for quantitative histochemistry. J Histochem Cytochem 65:153–171. PMID: 28080173, PMCID: PMC5298458.

  66. Bhattacherjee A, Djekidel MN, Chen R, Chen W, Tuesta LM, Zhang Y. Cell type-specific transcriptional programs in mouse prefrontal cortex during adolescence and addiction. Nat Commun. 2019;10:1–18. https://doi.org/10.1038/s41467-019-12054-3.

  67. Tigges J, Gordon TP, McClure HM, Hall EC, Peters A. Survival rate and life span of rhesus monkeys at the Yerkes regional primate research center. Am J Primatol. 1988;15:263–73. https://doi.org/10.1002/ajp.1350150308.

    Article  PubMed  Google Scholar 

  68. Gearing M, Tigges J, Mori H, Mirra SS. A beta40 is a major form of beta-amyloid in nonhuman primates. Neurobiol Aging. 1996;17:903–8. https://doi.org/10.1016/s0197-4580(96)00164-9.

    Article  CAS  PubMed  Google Scholar 

  69. Zheng W, Tsai MY, Wolynes PG. Comparing the aggregation free energy landscapes of amyloid Beta(1-42) and amyloid Beta(1-40). J Am Chem Soc. 2017;139:16666–76. https://doi.org/10.1021/jacs.7b08089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Edmonds EC, Bangen KJ, Delano-Wood L, Nation DA, Furst AJ, Salmon DP, et al. Patterns of cortical and subcortical amyloid burden across stages of preclinical Alzheimer’s disease. J Int Neuropsychol Soc. 2016;22:978–90. https://doi.org/10.1017/S1355617716000928.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Sloane JA, Pietropaolo MF, Rosene DL, Moss MB, Peters A, Kemper T, et al. Lack of correlation between plaque burden and cognition in the aged monkey. Acta Neuropathol. 1997;94:471–8. https://doi.org/10.1007/s004010050735.

    Article  CAS  PubMed  Google Scholar 

  72. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608. https://doi.org/10.15252/emmm.201606210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain. 2008;131:1630–45. https://doi.org/10.1093/brain/awn016.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Gusel’nikova VV, Korzhevskiy DE. NeuN as a neuronal nuclear antigen and neuron differentiation marker. Acta Naturae. 2015;7:42–7. https://doi.org/10.32607/20758251-2015-7-2-42-47.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Kim KK, Adelstein RS, Kawamoto S. Identification of neuronal nuclei (NeuN) as Fox-3, a new member of the Fox-1 gene family of splicing factors. J Biol Chem. 2009;284:31052–61. https://doi.org/10.1074/jbc.M109.052969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gittins R, Harrison PJ. Neuronal density, size and shape in the human anterior cingulate cortex: a comparison of Nissl and NeuN staining. Brain Res Bull. 2004;63:155–60. https://doi.org/10.1016/j.brainresbull.2004.02.005.

    Article  PubMed  Google Scholar 

  77. Duan W, Zhang YP, Hou Z, Huang C, Zhu H, Zhang CQ, et al. Novel insights into NeuN: from neuronal marker to splicing regulator. Mol Neurobiol. 2016;53:1637–47. https://doi.org/10.1007/s12035-015-9122-5.

    Article  CAS  PubMed  Google Scholar 

  78. Cruz E, Kumar S, Yuan L, Arikkath J, Batra SK. Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis. PLoS One. 2018;13:1–21. https://doi.org/10.1371/journal.pone.0191696.

    Article  CAS  Google Scholar 

  79. Kimura N, Yanagisawa K, Terao K, Ono F, Sakakibara I, Ishii Y, et al. Age-related changes of intracellular Aβ in cynomolgus monkey brains. Neuropathol Appl Neurobiol. 2005;31:170–80. https://doi.org/10.1111/j.1365-2990.2004.00624.x.

    Article  CAS  PubMed  Google Scholar 

  80. LaFerla FM, Green KN, Oddo S. Intracellular amyloid-β in Alzheimer’s disease. Nat Rev Neurosci. 2007;8:499–509. https://doi.org/10.1038/nrn2168.

    Article  CAS  PubMed  Google Scholar 

  81. Martin LJ, Sisodia SS, Koo EH, Cork LC, Dellovade TL, Weidemann A, et al. Amyloid precursor protein in aged nonhuman primates. Proc Natl Acad Sci U S A. 1991;88:1461–5. https://doi.org/10.1073/pnas.88.4.1461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Luebke J, Barbas H, Peters A. Effects of normal aging on prefrontal area 46 in the rhesus monkey. Brain Res Rev. 2010;62:212–32. https://doi.org/10.1016/j.brainresrev.2009.12.002.

    Article  PubMed  Google Scholar 

  83. Willette AA, Coe CL, Birdsill AC, Bendlin BB, Colman RJ, Alexander AL, et al. Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques. Age (Omaha). 2013;35:2215–27. https://doi.org/10.1007/s11357-013-9518-y.

    Article  CAS  Google Scholar 

  84. Harper JM, Leathers CW, Austad SN. Does caloric restriction extend life in wild mice? Aging Cell. 2006;5:441–9. https://doi.org/10.1111/j.1474-9726.2006.00236.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Schafer MJ, Alldred MJ, Lee SH, Calhoun ME, Petkova E, Mathews PM, et al. Reduction of β-amyloid and γ-secretase by calorie restriction in female Tg2576 mice. Neurobiol Aging. 2015;36:1293–302. https://doi.org/10.1016/j.neurobiolaging.2014.10.043.

    Article  CAS  PubMed  Google Scholar 

  86. Sridharan A, Pehar M, Salamat MS, Pugh TD, Bendlin BB, Willette AA, et al. Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: a preliminary quantitative imaging study. Brain Res. 2013;1508:1–8. https://doi.org/10.1038/jid.2014.371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Austad S N (2001) Does caloric restriction in the laboratory simply prevent overfeeding and return house mice to their natural level of food intake? Science 2001:pe3. https://doi.org/10.1126/sageke.2001.6.pe3.

  88. Le Bourg E. Does calorie restriction in primates increase lifespan? Revisiting studies on macaques (Macaca mulatta) and mouse lemurs (Microcebus murinus). BioEssays. 2018;40:e1800111. https://doi.org/10.1002/bies.201800111.

    Article  PubMed  Google Scholar 

  89. Major DE, Kesslak JP, Cotman CW, Finch CE, Day JR. Life-long dietary restriction attenuates age-related increases in hippocampal glial fibrillary acidic protein mRNA. Neurobiol Aging. 1997;18:523–6. https://doi.org/10.1016/s0197-4580(97)00102-4.

    Article  CAS  PubMed  Google Scholar 

  90. Nelson PT, Alafuzoff I, Bigio E, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362–81. https://doi.org/10.1097/NEN.0b013e31825018f7.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Kastman EK, Willette AA, Coe CL, Bendlin BB, Kosmatka KJ, McLaren DG, et al. A calorie-restricted diet decreases brain Iron accumulation and preserves motor performance in old rhesus monkeys. J Neurosci. 2012;32:11897–904. https://doi.org/10.1523/JNEUROSCI.2553-12.2012.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Zhang J, Chen B, Lu J, Wu Y, Wang S, Yao Z, et al. Brains of rhesus monkeys display Aβ deposits and glial pathology while lacking dimers and other Alzheimer’s pathologies. Aging Cell. 2018;18:e12978. https://doi.org/10.1111/acel.12978.

    Article  CAS  Google Scholar 

  93. Beckman D, Ott S, Donis-Cox K, Janssen WG, Bliss-Moreau E, Rudebeck PH, et al. Oligomeric Aβ in the monkey brain impacts synaptic integrity and unduces accelerated cortical aging. PNAS. 2019;116:26239–46.

    Article  CAS  Google Scholar 

  94. Forny-Germano L, Lyra eSilva NM, Batista AF, Brito-Moreira J, Gralle M, Boehnke SE, et al. Alzheimer’s disease-like pathology induced by amyloid-β oligomer in nonhuman primates. J Neurosci. 2014;34:13629–43.

    Article  Google Scholar 

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Acknowledgments

The authors would like to acknowledge the contributions of Dr. Sathya Srinivasan in the Imaging and Histology core at the Oregon National Primate Research Center for his expertise in stereological methodology.

Code availability

Not applicable.

Funding

This work was supported by the National Institutes of Health (NIH) grants AG043640, AG055378, AG062220, OD011092 and the Intramural Research Program, National Institute on Aging, NIH.

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Authors and Affiliations

  1. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA

    GA Stonebarger & HF Urbanski

  2. Division of Neuroscience, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR, 97006, USA

    GA Stonebarger, HF Urbanski & SG Kohama

  3. Department of Pathology, Oregon Health & Science University, Portland, OR, 97239, USA

    RL Woltjer

  4. Translational Gerontology Branch, National Institute on Aging Intramural Research Program, NIH, Dickerson, MD, 20842, USA

    KL Vaughan & JA Mattison

  5. Charles River, Wilmington, MA, 01867, USA

    KL Vaughan

  6. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, 70808, USA

    DK Ingram

  7. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MD, 02218, USA

    PL Schultz, SM Calderazzo, JA Siedeman & DL Rosene

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  1. GA Stonebarger
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  2. HF Urbanski
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  7. SM Calderazzo
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  10. DL Rosene
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  11. SG Kohama
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Corresponding author

Correspondence to SG Kohama.

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This study makes use of animal tissue from a study approved by the National Institute on Aging Intramural Research Program Animal Care and Use Committee.

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Stonebarger, G., Urbanski, H., Woltjer, R. et al. Amyloidosis increase is not attenuated by long-term calorie restriction or related to neuron density in the prefrontal cortex of extremely aged rhesus macaques. GeroScience 42, 1733–1749 (2020). https://doi.org/10.1007/s11357-020-00259-0

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