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Cited by 138Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment and Alzheimer's disease

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Vana, Laurel, Kanaan, Nicholas M., Ugwu, Isabella C., Wuu, Joanne, Mufson, Elliott J., Binder, Lester I.·2011·The American Journal of Pathology
DOI 10.1016/j.ajpath.2011.07.044PMC PMC3204017
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Abstract

Tau is a microtubule-associated protein that forms neurofibrillary tangles (NFTs) in the selective vulnerable long projection neurons of the cholinergic basal forebrain (CBF) in Alzheimer's disease (AD). Although CBF neurodegeneration correlates with cognitive decline during AD progression, little is known about the temporal changes of tau accumulation in this region. We investigated tau posttranslational modifications during NFT evolution within the CBF neurons of the nucleus basalis (NB) using tissue from subjects with no cognitive impairment, mild cognitive impairment, and AD. The pS422 antibody was used as an early tau pathology marker that labels tau phosphorylated at Ser422; the TauC3 antibody was used to detect later stage tau pathology. Stereologic evaluation of NB tissue immunostained for pS422 and TauC3 revealed an increase in neurons expressing these tau epitopes during disease progression. We also investigated the occurrence of pretangle tau events within cholinergic NB neurons by dual staining for the cholinergic cell marker, p75(NTR), which displays a phenotypic down-regulation within CBF perikarya in AD. As pS422+ neurons increased in number, p75(NTR)+ neurons decreased, and these changes correlated with both AD neuropathology and cognitive decline. Also, NFTs developed slower in the CBF compared with previously examined cortical regions. Taken together, these results suggest that changes in cognition are associated with pretangle events within NB cholinergic neurons before frank NFT deposition.

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  • Previous studies have shown that EpoD and NAP can reduce p-tau pathology in AD model mice over several months of treatment.

    “Additionally, previous studies utilizing EpoD as well as microtubule-stabilizing peptide NAP have both shown ability to reduce p-tau pathology in AD model mice over several months of treatment 31,66,67”

    From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [67]

    The paper describes tau pathology in human nucleus basalis tissue from people with no cognitive impairment, mild cognitive impairment, or Alzheimer’s disease. Searches for EpoD and NAP found no passage about either treatment reducing phosphorylated tau in AD-model mice over several months. (LLM, conf=0.75)

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References 88 · Cited by 138

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  1. Mesulam MM, Geula C: Nucleus basalis (Ch4) and cortical cholin- ergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol 1988, 275:216 -240
  2. Wilcock GK, Esiri MM: Plaques, tangles and dementia. A quantitative study. J Neurol Sci 1982, 56:343-356
  3. Bierer LM, Haroutunian V, Gabriel S, Knott PJ, Carlin LS, Purohit DP, Perl DP, Schmeidler J, Kanof P, Davis KL: Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits. J Neurochem 1995, 64:749 -760
  4. McGeer PL, McGeer EG, Suzuki J, Dolman CE, Nagai T: Aging. Alzheimer's disease, and the cholinergic system of the basal fore- brain. Neurology 1984, 34:741-745
  5. Tagliavini F, Pilleri G: Neuronal counts in basal nucleus of Meynert in Alzheimer disease and in simple senile dementia. Lancet 1983, 1:469 -470
  6. Arendt T, Bigl V, Tennstedt A, Arendt A: Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer's disease. Neuroscience 1985, 14:1-14
  7. Mufson EJ, Bothwell M, Kordower JH: Loss of nerve growth factor receptor-containing neurons in Alzheimer's disease: a quantitative analysis across subregions of the basal forebrain. Exp Neurol 1989, 105:221-232
  8. Hefti F: Is Alzheimer disease caused by lack of nerve growth factor? Ann Neurol 1983, 13:109 -110
  9. Teng KK, Hempstead BL: Neurotrophins and their receptors: signal- ing trios in complex biological systems. Cell Mol Life Sci 2004, 61: 35-48
  10. Mufson EJ, Ma SY, Cochran EJ, Bennett DA, Beckett LA, Jaffar S, Saragovi HU, Kordower JH: Loss of nucleus basalis neurons contain- ing trkA immunoreactivity in individuals with mild cognitive impair- ment and early Alzheimer's disease. J Comp Neurol 2000, 427:19 -30
  11. Mufson EJ, Ma SY, Dills J, Cochran EJ, Leurgans S, Wuu J, Bennett DA, Jaffar S, Gilmor ML, Levey AI, Kordower JH: Loss of basal forebrain P75(NTR) immunoreactivity in subjects with mild cognitive impairment and Alzheimer's disease. J Comp Neurol 2002, 443:136 - 153
  12. Sassin I, Schultz C, Thal DR, Rub U, Arai K, Braak E, Braak H: Evolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert. Acta Neuropathol (Berl) 2000, 100:259 - 269
  13. Wu CK, Thal L, Pizzo D, Hansen L, Masliah E, Geula C: Apoptotic signals within the basal forebrain cholinergic neurons in Alzheimer's disease. Exp Neurol 2005, 195:484 -496
  14. Mesulam M, Shaw P, Mash D, Weintraub S: Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann Neurol 2004, 55:815-828
  15. Johnson GVW, Hartigan JA: Tau protein in normal and Alzheimer's disease brain: an update. Alzheimer Dis Rev 1998, 3:125-141
  16. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR: Tau protein isoforms, phosphorylation and the role in neurodegenerative disorders. Brain Res Brain Res Rev 2000, 33:95-130
  17. Spillantini MG, Goedert M: Tau protein pathology in neurodegenera- tive diseases. Trends Neurosci 1998, 21:428 -433 2548
  18. Vana et al AJP November 2011, Vol. 179, No. 5
  19. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI: Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA: 1986, 83:4913-4917
  20. Wood JG, Mirra SS, Pollock NJ, Binder LI: Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal mi- crotubule-associated protein tau (tau) [published erratum appears in Proc Natl Acad Sci USA 1986;83:9773]. Proc Natl Acad Sci USA 1986, 83:4040 -4043
  21. Alonso AC, Grundke-Iqbal I, Iqbal K: Alzheimer's disease hyperphos- phorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 1996, 2:783-787
  22. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL: Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci USA: 2003, 100:10032-10037
  23. Ghoshal N, Garcia-Sierra F, Wuu J, Leurgans S, Bennett DA, Berry RW, Binder LI: Tau conformational changes correspond to impair- ments of episodic memory in mild cognitive impairment and Alzhei- mer's disease. Exp Neurol 2002, 177:475-493
  24. Garcia-Sierra F, Ghoshal N, Quinn B, Berry RW, Binder LI: Confor- mational changes and truncation of tau protein during tangle evolu- tion in Alzheimer's disease. J Alzheimer's Dis 2003, 5:65-77
  25. Guillozet-Bongaarts AL, Garcia-Sierra F, Reynolds MR, Horowitz PM, Fu Y, Wang T, Cahill ME, Bigio EH, Berry RW, Binder LI: Tau trunca- tion during neurofibrillary tangle evolution in Alzheimer's disease. Neurobiol Aging 2005, 26:1015-1022
  26. Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW: Tau, tangles, and Alzheimer's disease. Biochim Biophys Acta 2005, 1739: 216 -223
  27. Guillozet-Bongaarts AL, Cahill ME, Cryns VL, Reynolds MR, Berry RW, Binder LI: Pseudophosphorylation of tau at serine422 inhibits caspase cleavage: in vitro evidence and implications for tangle for- mation in vivo. J Neurochem 2006, 97:1005-1014
  28. Guillozet-Bongaarts AL, Glajch KE, Libson EG, Cahill ME, Bigio E, Berry RW, Binder LI: Phosphorylation and cleavage of tau in non-AD tauopathies. Acta Neuropathol 2007, 113:513-520
  29. Geula C, Nagykery N, Nicholas A, Wu CK: Cholinergic neuronal and axonal abnormalities are present early in aging and in Alzheimer disease. J Neuropathol Exp Neurol 2008, 67:309 -318
  30. LaPointe NE, Morfini G, Pigino G, Gaisina IN, Kozikowski AP, Binder LI, Brady ST: The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J Neurosci Res 2009, 87:440 -451
  31. Su JH, Deng G, Cotman CW: Transneuronal degeneration in the spread of Alzheimer's disease pathology: immunohistochemical evi- dence for the transmission of tau hyperphosphorylation. Neurobiol Dis 1997, 4:365-375
  32. Mufson EJ, Chen EY, Cochran EJ, Beckett LA, Bennett DA, Kordower JH: Entorhinal cortex beta-amyloid load in individuals with mild cog- nitive impairment. Exp Neurol 1999, 158:469 -490
  33. Gilmor ML, Erickson JD, Varoqui H, Hersh LB, Bennett DA, Cochran EJ, Mufson EJ, Levey AI: Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer's disease. J Comp Neurol 1999, 411:693-704
  34. Kordower JH, Chu Y, Stebbins GT, DeKosky ST, Cochran EJ, Bennett D, Mufson EJ: Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 2001, 49:202-213
  35. Bennett DA, Shannon KM, Beckett LA, Goetz CG, Wilson RS: Metric properties of nurses' ratings of parkinsonian signs with a modified Unified Parkinson's Disease Rating Scale. Neurology 1997, 49:1580 - 1587
  36. Bennett DA, Shannon KM, Beckett LA, Wilson RS: Dimensionality of parkinsonian signs in aging and Alzheimer's disease. J Gerontol A Biol Sci Med Sci 1999, 54:M191-M196
  37. Benton AL, Varney NR, Hamsher KD: Visuospatial judgment. A clin- ical test. Arch Neurol 1978, 35:364 -367
  38. Albert M, Smith LA, Scherr PA, Taylor JO, Evans DA, Funkenstein HH: Use of brief cognitive tests to identify individuals in the community with clinically diagnosed Alzheimer's disease. Int J Neurosci 1991, 57:167-178
  39. Willshire D, Kinsella G, Prior M: Estimating WAIS-R IQ from the Na- tional Adult Reading Test: a cross-validation. J Clin Exp Neuropsy- chol 1991, 13:204 -216
  40. Welsh KA, Butters N, Hughes JP, Mohs RC, Heyman A: Detection and staging of dementia in Alzheimer's disease. Use of the neuropsycho- logical measures developed for the Consortium to Establish a Reg- istry for Alzheimer's Disease. Arch Neurol 1992, 49:448 -452
  41. Cooper JA, Sagar HJ: Incidental and intentional recall in Parkinson's disease: an account based on diminished attentional resources. J Clin Exp Neuropsychol 1993, 15:713-731
  42. Pittman J, Andrews H, Tatemichi T, Link B, Struening E, Stern Y, Mayeux R: Diagnosis of dementia in a heterogeneous population. A comparison of paradigm-based diagnosis and physician's diagnosis. Arch Neurol 1992, 49:461-467
  43. Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR: Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study. JAMA 1996, 275:528 -532
  44. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer's disease: report of the NINCDS- ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984, 34:939 -944
  45. Rubin EH, Morris JC, Grant EA, Vendegna T: Very mild senile demen- tia of the Alzheimer type. I Clinical assessment. Arch Neurol 1989, 46:379 -382
  46. Petersen RC, Smith GE, Ivnik RJ, Tangalos EG, Schaid DJ, Thibodeau SN, Kokmen E, Waring SC, Kurland LT: Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory- impaired individuals. JAMA 1995, 273:1274 -1278
  47. Devanand DP, Folz M, Gorlyn M, Moeller JR, Stern Y: Questionable dementia: clinical course and predictors of outcome. J Am Geriatr Soc 1997, 45:321-328
  48. Cochran EJ, Fox JH, Mufson EJ: Severe panencephalic Pick's dis- ease with Alzheimer's disease-like neuropil threads and synaptophy- sin immunoreactivity. Acta Neuropathol 1994, 88:479 -484
  49. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L: The Consortium to Estab- lish a Registry for Alzheimer's Disease (CERAD). Part II: Standard- ization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991, 41:479 -486
  50. Kins S, Crameri A, Evans DR, Hemmings BA, Nitsch RM, Gotz J: Reduced protein phosphatase 2A activity induces hyperphosphory- lation and altered compartmentalization of tau in transgenic mice. J Biol Chem 2001, 276:38193-38200
  51. Hasegawa M, Jakes R, Crowther RA, Lee VM, Ihara Y, Goedert M: Characterization of mAb AP422, a novel phosphorylation-dependent monoclonal antibody against tau protein. FEBS Lett 1996, 384:25-30
  52. Reynolds CH, Utton MA, Gibb GM, Yates A, Anderton BH: Stress- activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein. J Neurochem 1997, 68:1736 -1744
  53. Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K: Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neuro- Tau Pathology within Cholinergic Neurons 2549 AJP November 2011, Vol. 179, No. 5 fibrillary degeneration in Alzheimer's disease. J Biol Chem 2000, 275:5535-5544
  54. Kimura T, Ono T, Takamatsu J, Yamamoto H, Ikegami K, Kondo A, Hasegawa M, Ihara Y, Miyamoto E, Miyakawa T: Sequential changes of tau-site-specific phosphorylation during development of paired helical filaments. Dementia 1996, 7:177-181
  55. Schatteman GC, Gibbs L, Lanahan AA, Claude P, Bothwell M: Ex- pression of NGF receptor in the developing and adult primate central nervous system. J Neurosci 1988, 8:860 -873
  56. Kordower JH, Bartus RT, Bothwell M, Schatteman G, Gash DM: Nerve growth factor receptor immunoreactivity in the nonhuman primate (Cebus apella): distribution, morphology, and colocalization with cho- linergic enzymes. J Comp Neurol 1988, 277:465-486
  57. Mesulam MM, Mufson EJ, Wainer BH, Levey AI: Central cholinergic pathways in the rat: an overview based on an alternative nomencla- ture (Ch1-Ch6). Neuroscience 1983, 10:1185-1201
  58. Gundersen HJ, Bagger P, Bendtsen TF, Evans SM, Korbo L, Marcus- sen N, Moller A, Nielsen K, Nyengaard JR, Pakkenberg B: The new stereological tools: disector, fractionator, nucleator and point sam- pled intercepts and their use in pathological research and diagnosis. APMIS 1988, 96:857-881
  59. Pakkenberg B, Moller A, Gundersen HJ, Mouritzen Dam A, Pakken- berg H: The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method. J Neurol Neurosurg Psychi- atry 1991, 54:30 -33
  60. Kanaan NM, Kordower JH, Collier TJ: Age-related accumulation of Marinesco bodies and lipofuscin in rhesus monkey midbrain dopa- mine neurons: relevance to selective neuronal vulnerability. J Comp Neurol 2007, 502:683-700
  61. West MJ: New stereological methods for counting neurons. Neurobiol Aging 1993, 14:275-285
  62. West MJ: Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci 1999, 22:51-61
  63. Mouton PR, Gokhale AM, Ward NL, West MJ: Stereological length estimation using spherical probes. J Microsc 2002, 206:54 -64
  64. Markesbery WR: Neuropathologic alterations in mild cognitive impairment: a review. J Alzheimers Dis 2010, 19:221-228
  65. Mufson EJ, Counts SE, Perez SE, Ginsberg SD: Cholinergic system during the progression of Alzheimer's disease: therapeutic implica- tions. Expert Rev Neurother 2008, 8:1703-1718
  66. Geula C, Nagykery N, Wu CK, Bu J: Loss of calbindin-D28K from aging human cholinergic basal forebrain: relation to plaques and tangles. J Neuropathol Exp Neurol 2003, 62:605-616
  67. DeKosky ST, Ikonomovic MD, Styren SD, Beckett L, Wisniewski S, Bennett DA, Cochran EJ, Kordower JH, Mufson EJ: Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002, 51:145-155
  68. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E: Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999, 56:303-308
  69. Luis CA, Loewenstein DA, Acevedo A, Barker WW, Duara R: Mild cognitive impairment: directions for future research. Neurology 2003, 61:438 -444
  70. Vana et al AJP November 2011, Vol. 179, No. 5

Authors
Vana, L., Kanaan, N. M., Ugwu, I. C., Wuu, J., Mufson, E. J., & Binder, L. I.
Affiliations
  • Northwestern University (US)
  • Michigan State University (US)
  • University of Miami (US)
  • Rush University Medical Center (US)
Corresponding author
Vana, Laurel
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2011-11
Volume
179
Issue
5
Pages
2533-2550
ISSN
0002-9440 (ISSN-L)
DOI
10.1016/j.ajpath.2011.07.044
PMC
PMC3204017
OpenAlex
W2054354293
Cited by
138
References
88
Citations by year
2026: 7 · 2025: 16 · 2024: 11 · 2023: 9 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 10 · 2018: 5 · 2017: 6 · 2016: 11 · 2015: 10 · 2014: 11 · 2013: 11 · 2012: 6
FWCI
6.76
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (AG09466, P01AG14449)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tau pathology, neurofibrillary tangles, nucleus basalis of Meynert, Alzheimer's disease, mild cognitive impairment, p75 neurotrophin receptor, disease progression, cognitive decline, stereology
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Antibodies, Monoclonal, Female, Humans, Male, Biomarkers, Prosencephalon, tau Proteins, Disease Progression, Cholinergic Neurons, Cognitive Dysfunction

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