Preserved autophagy in cognitively intact non-demented individuals with Alzheimer's neuropathology

doi:10.1002/alz.13074

. 2023 Dec;19(12):5355-5370.

doi: 10.1002/alz.13074. Epub 2023 May 16.

Preserved autophagy in cognitively intact non-demented individuals with Alzheimer's neuropathology

Batbayar Tumurbaatar¹, Anna Fracassi¹, Pietro Scaduto¹, Jutatip Guptarak¹, Randall Woltjer², Daniel Jupiter³, Giulio Taglialatela¹

Affiliations

¹ Mitchell Center for Neurodegenerative Diseases, Department of Neurology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA.
² Department of Pathology, Oregon Health and Science University, Portland, Oregon, USA.
³ Department of Biostatistics & Data Science, Department of Orthopaedic Surgery and Rehabilitation, University of Texas Medical Branch (UTMB), Galveston, Texas, USA.

PMID: 37191183
PMCID: PMC10651802 (available on 2024-12-01)
DOI: 10.1002/alz.13074

Preserved autophagy in cognitively intact non-demented individuals with Alzheimer's neuropathology

Batbayar Tumurbaatar et al. Alzheimers Dement. 2023 Dec.

. 2023 Dec;19(12):5355-5370.

doi: 10.1002/alz.13074. Epub 2023 May 16.

Authors

Batbayar Tumurbaatar¹, Anna Fracassi¹, Pietro Scaduto¹, Jutatip Guptarak¹, Randall Woltjer², Daniel Jupiter³, Giulio Taglialatela¹

Affiliations

¹ Mitchell Center for Neurodegenerative Diseases, Department of Neurology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA.
² Department of Pathology, Oregon Health and Science University, Portland, Oregon, USA.
³ Department of Biostatistics & Data Science, Department of Orthopaedic Surgery and Rehabilitation, University of Texas Medical Branch (UTMB), Galveston, Texas, USA.

PMID: 37191183
PMCID: PMC10651802 (available on 2024-12-01)
DOI: 10.1002/alz.13074

Abstract

Introduction: Growing evidence supports that dysfunctional autophagy, the major cell mechanism responsible for removing protein aggregates and a route of clearance for Tau in healthy neurons, is a major finding in demented Alzheimer's disease (AD) patients. However, the association of autophagy with maintenance of cognitive integrity in resilient individuals who have AD neuropathology but remain non-demented (NDAN) has not been evaluated.

Methods: Using post mortem brain samples from age-matched healthy control, AD, and NDAN subjects, we evaluated autophagy in relation to Tau pathology using Western blot, immunofluorescence and RNA-seq.

Results: Compared to AD patients, NDAN subjects had preserved autophagy and reduced tauopathy. Furthermore, expression of autophagy genes and AD-related proteins were significantly associated in NDAN compared to AD and control subjects.

Discussion: Our results suggest preserved autophagy is a protective mechanism that maintains cognitive integrity in NDAN individuals. This novel observation supports the potential of autophagy-inducing strategies in AD therapeutics.

Highlights: NDAN subjects have preserved autophagic protein levels comparable with control subjects. Compared to control subjects, NDAN subjects have significantly reduced Tau oligomers and PHF Tau phosphorylation at synapses that negatively correlate with autophagy markers. Transcription of autophagy genes strongly associates with AD-related proteins in NDAN donors.

Keywords: Alzheimer's disease; Tau; autophagy; resilience.

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Conflict of interest statement

CONFLICT OF INTERESTS

The authors declare no competing interests.

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References

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[1] 2020 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia [Internet]. 2020. Mar 1 [cited 2021 Jul 5];16(3):391–460. Available from: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12068 - DOI

[2] 2020 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia [Internet]. 2020. Mar 1 [cited 2021 Jul 5];16(3):391–460. Available from: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12068 - DOI

[3] Glenner GG, Wong CW. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984. May 16;120(3):885–90. - PubMed

[4] Glenner GG, Wong CW. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984. May 16;120(3):885–90. - PubMed

[5] 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. Proceedings of the National Academy of Sciences [Internet]. 1986. Jul 1 [cited 2023 Feb 13];83(13):4913–7. Available from: https://www.pnas.org/doi/abs/10.1073/pnas.83.13.4913 - DOI - PMC - PubMed

[6] 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. Proceedings of the National Academy of Sciences [Internet]. 1986. Jul 1 [cited 2023 Feb 13];83(13):4913–7. Available from: https://www.pnas.org/doi/abs/10.1073/pnas.83.13.4913 - DOI - PMC - PubMed

[7] Querfurth HW, LaFerla FM. Alzheimer’s Disease. https://doi.org/101056/NEJMra0909142 [Internet]. 2010. Jan 28 [cited 2022 Dec 11];362(4):329–44. Available from: https://www.nejm.org/doi/10.1056/NEJMra0909142 - DOI - PubMed

[8] Querfurth HW, LaFerla FM. Alzheimer’s Disease. https://doi.org/101056/NEJMra0909142 [Internet]. 2010. Jan 28 [cited 2022 Dec 11];362(4):329–44. Available from: https://www.nejm.org/doi/10.1056/NEJMra0909142 - DOI - PubMed

[9] Nelson PT, Alafuzoff I, Bigio EH, 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 [Internet]. 2012. May [cited 2018 Nov 18];71(5):362–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22487856 - PMC - PubMed

[10] Nelson PT, Alafuzoff I, Bigio EH, 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 [Internet]. 2012. May [cited 2018 Nov 18];71(5):362–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22487856 - PMC - PubMed

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Preserved autophagy in cognitively intact non-demented individuals with Alzheimer's neuropathology

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Preserved autophagy in cognitively intact non-demented individuals with Alzheimer's neuropathology

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