Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain

Abstract Background Mitochondrial dysfunction is a feature of neurodegenerative diseases, including Alzheimer’s disease (AD). Changes in the mitochondrial DNA copy number (mtDNAcn) and increased mitochondrial DNA mutation burden have both been associated with neurodegenerative diseases and cognitive...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Hans-Ulrich Klein, Caroline Trumpff, Hyun-Sik Yang, Annie J. Lee, Martin Picard, David A. Bennett, Philip L. De Jager
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Mitochondria Neurodegeneration Alzheimer’s disease Mitochondrial DNA copy number Mitochondrial heteroplasmy Tau Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/838182d8c8224a2495fb01b890d7243e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:838182d8c8224a2495fb01b890d7243e
record_format	dspace
spelling	oai:doaj.org-article:838182d8c8224a2495fb01b890d7243e2021-11-08T10:45:23ZCharacterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain10.1186/s13024-021-00495-81750-1326https://doaj.org/article/838182d8c8224a2495fb01b890d7243e2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13024-021-00495-8https://doaj.org/toc/1750-1326Abstract Background Mitochondrial dysfunction is a feature of neurodegenerative diseases, including Alzheimer’s disease (AD). Changes in the mitochondrial DNA copy number (mtDNAcn) and increased mitochondrial DNA mutation burden have both been associated with neurodegenerative diseases and cognitive decline. This study aims to systematically identify which common brain pathologies in the aged human brain are associated with mitochondrial recalibrations and to disentangle the relationship between these pathologies, mtDNAcn, mtDNA heteroplasmy, aging, neuronal loss, and cognitive function. Methods Whole-genome sequencing data from n = 1361 human brain samples from 5 different regions were used to quantify mtDNAcn as well as heteroplasmic mtDNA point mutations and small indels. Brain samples were assessed for 10 common pathologies. Annual cognitive test results were used to assess cognitive function proximal to death. For a subset of samples, neuronal proportions were estimated from RNA-seq profiles, and mass spectrometry was used to quantify the mitochondrial protein content of the tissue. Results mtDNAcn was 7–14% lower in AD relative to control participants. When accounting for all 10 common neuropathologies, only tau was significantly associated with lower mtDNAcn in the dorsolateral prefrontal cortex. In the posterior cingulate cortex, TDP-43 pathology demonstrated a distinct association with mtDNAcn. No changes were observed in the cerebellum, which is affected late by pathologies. Neither age nor gender was associated with mtDNAcn in the studied brain regions when adjusting for pathologies. Mitochondrial content and mtDNAcn independently explained variance in cognitive function unaccounted by pathologies, implicating complex mitochondrial recalibrations in cognitive decline. In contrast, mtDNA heteroplasmy levels increased by 1.5% per year of life in the cortical regions, but displayed no association with any of the pathologies or cognitive function. Conclusions We studied mtDNA quantity and quality in relation to mixed pathologies of aging and showed that tau and not amyloid-β is primarily associated with reduced mtDNAcn. In the posterior cingulate cortex, the association of TDP-43 with low mtDNAcn points to a vulnerability of this region in limbic-predominant age-related TDP-43 encephalopathy. While we found low mtDNAcn in brain regions affected by pathologies, the absence of associations with mtDNA heteroplasmy burden indicates that mtDNA point mutations and small indels are unlikely to be involved in the pathogenesis of late-onset neurodegenerative diseases.Hans-Ulrich KleinCaroline TrumpffHyun-Sik YangAnnie J. LeeMartin PicardDavid A. BennettPhilip L. De JagerBMCarticleMitochondriaNeurodegenerationAlzheimer’s diseaseMitochondrial DNA copy numberMitochondrial heteroplasmyTauNeurology. Diseases of the nervous systemRC346-429GeriatricsRC952-954.6ENMolecular Neurodegeneration, Vol 16, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mitochondria Neurodegeneration Alzheimer’s disease Mitochondrial DNA copy number Mitochondrial heteroplasmy Tau Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6
spellingShingle	Mitochondria Neurodegeneration Alzheimer’s disease Mitochondrial DNA copy number Mitochondrial heteroplasmy Tau Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6 Hans-Ulrich Klein Caroline Trumpff Hyun-Sik Yang Annie J. Lee Martin Picard David A. Bennett Philip L. De Jager Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain
description	Abstract Background Mitochondrial dysfunction is a feature of neurodegenerative diseases, including Alzheimer’s disease (AD). Changes in the mitochondrial DNA copy number (mtDNAcn) and increased mitochondrial DNA mutation burden have both been associated with neurodegenerative diseases and cognitive decline. This study aims to systematically identify which common brain pathologies in the aged human brain are associated with mitochondrial recalibrations and to disentangle the relationship between these pathologies, mtDNAcn, mtDNA heteroplasmy, aging, neuronal loss, and cognitive function. Methods Whole-genome sequencing data from n = 1361 human brain samples from 5 different regions were used to quantify mtDNAcn as well as heteroplasmic mtDNA point mutations and small indels. Brain samples were assessed for 10 common pathologies. Annual cognitive test results were used to assess cognitive function proximal to death. For a subset of samples, neuronal proportions were estimated from RNA-seq profiles, and mass spectrometry was used to quantify the mitochondrial protein content of the tissue. Results mtDNAcn was 7–14% lower in AD relative to control participants. When accounting for all 10 common neuropathologies, only tau was significantly associated with lower mtDNAcn in the dorsolateral prefrontal cortex. In the posterior cingulate cortex, TDP-43 pathology demonstrated a distinct association with mtDNAcn. No changes were observed in the cerebellum, which is affected late by pathologies. Neither age nor gender was associated with mtDNAcn in the studied brain regions when adjusting for pathologies. Mitochondrial content and mtDNAcn independently explained variance in cognitive function unaccounted by pathologies, implicating complex mitochondrial recalibrations in cognitive decline. In contrast, mtDNA heteroplasmy levels increased by 1.5% per year of life in the cortical regions, but displayed no association with any of the pathologies or cognitive function. Conclusions We studied mtDNA quantity and quality in relation to mixed pathologies of aging and showed that tau and not amyloid-β is primarily associated with reduced mtDNAcn. In the posterior cingulate cortex, the association of TDP-43 with low mtDNAcn points to a vulnerability of this region in limbic-predominant age-related TDP-43 encephalopathy. While we found low mtDNAcn in brain regions affected by pathologies, the absence of associations with mtDNA heteroplasmy burden indicates that mtDNA point mutations and small indels are unlikely to be involved in the pathogenesis of late-onset neurodegenerative diseases.
format	article
author	Hans-Ulrich Klein Caroline Trumpff Hyun-Sik Yang Annie J. Lee Martin Picard David A. Bennett Philip L. De Jager
author_facet	Hans-Ulrich Klein Caroline Trumpff Hyun-Sik Yang Annie J. Lee Martin Picard David A. Bennett Philip L. De Jager
author_sort	Hans-Ulrich Klein
title	Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain
title_short	Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain
title_full	Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain
title_fullStr	Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain
title_full_unstemmed	Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain
title_sort	characterization of mitochondrial dna quantity and quality in the human aged and alzheimer’s disease brain
publisher	BMC
publishDate	2021
url	https://doaj.org/article/838182d8c8224a2495fb01b890d7243e
work_keys_str_mv	AT hansulrichklein characterizationofmitochondrialdnaquantityandqualityinthehumanagedandalzheimersdiseasebrain AT carolinetrumpff characterizationofmitochondrialdnaquantityandqualityinthehumanagedandalzheimersdiseasebrain AT hyunsikyang characterizationofmitochondrialdnaquantityandqualityinthehumanagedandalzheimersdiseasebrain AT anniejlee characterizationofmitochondrialdnaquantityandqualityinthehumanagedandalzheimersdiseasebrain AT martinpicard characterizationofmitochondrialdnaquantityandqualityinthehumanagedandalzheimersdiseasebrain AT davidabennett characterizationofmitochondrialdnaquantityandqualityinthehumanagedandalzheimersdiseasebrain AT philipldejager characterizationofmitochondrialdnaquantityandqualityinthehumanagedandalzheimersdiseasebrain
_version_	1718442634031136768

Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain

Ejemplares similares