Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: Prevention by correcting lysosomal proteolytic deficits

Dun Sheng Yang, Philip Stavrides, Mitsuo Saito, Asok Kumar, Jose A. Rodriguez-Navarro, Monika Pawlik, Chunfeng Huo, Steven U. Walkley, Mariko Saito, Ana Maria Cuervo, Ralph A. Nixon

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Autophagy, the major lysosomal pathway for the turnover of intracellular organelles is markedly impaired in neurons in Alzheimer's disease and Alzheimer mouse models. We have previously reported that severe lysosomal and amyloid neuropathology and associated cognitive deficits in the TgCRND8 Alzheimer mouse model can be ameliorated by restoring lysosomal proteolytic capacity and autophagy flux via genetic deletion of the lysosomal protease inhibitor, cystatin B. Here we present evidence that macroautophagy is a significant pathway for lipid turnover, which is defective in TgCRND8 brain where lipids accumulate as membranous structures and lipid droplets within giant neuronal autolysosomes. Levels of multiple lipid species including several sphingolipids (ceramide, ganglioside GM3, GM2, GM1, GD3 and GD1a), cardiolipin, cholesterol and cholesteryl esters are elevated in autophagic vacuole fractions and lysosomes isolated from TgCRND8 brain. Lipids are localized in autophagosomes and autolysosomes by double immunofluorescence analyses in wild-type mice and colocalization is increased in TgCRND8 mice where abnormally abundant GM2 ganglioside-positive granules are detected in neuronal lysosomes. Cystatin B deletion in TgCRND8 significantly reduces the number of GM2-positive granules and lowers the levels of GM2 and GM3 in lysosomes, decreases lipofuscin-related autofluorescence, and eliminates giant lipid-containing autolysosomes while increasing numbers of normal-sized autolysosomes/lysosomes with reduced content of undigested components. These findings have identified macroautophagy as a previously unappreciated route for delivering membrane lipids to lysosomes for turnover, a function that has so far been considered to be mediated exclusively through the endocytic pathway, and revealed that autophagic-lysosomal dysfunction in TgCRND8 brain impedes lysosomal turnover of lipids as well as proteins. The amelioration of lipid accumulation in TgCRND8 by removing cystatin B inhibition on lysosomal proteases suggests that enhancing lysosomal proteolysis improves the overall environment of the lysosome and its clearance functions, which may be possibly relevant to a broader range of lysosomal disorders beyond Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)3300-3318
Number of pages19
JournalBrain
Volume137
Issue number12
DOIs
StatePublished - Dec 1 2014

Fingerprint

Lysosomes
Cystatin B
Lipids
Autophagy
Brain
G(M2) Ganglioside
Cholesterol Esters
Alzheimer Disease
G(M3) Ganglioside
Lipofuscin
Sphingolipids
Cardiolipins
Ceramides
Membrane Lipids
Vacuoles
Mouse
Alzheimer
Turnover
Protease Inhibitors
Amyloid

Keywords

  • Alzheimer's disease
  • Autophagy
  • Lipids
  • Lysosome
  • TgCRND8

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Yang, D. S., Stavrides, P., Saito, M., Kumar, A., Rodriguez-Navarro, J. A., Pawlik, M., ... Nixon, R. A. (2014). Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: Prevention by correcting lysosomal proteolytic deficits. Brain, 137(12), 3300-3318. https://doi.org/10.1093/brain/awu278

Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model : Prevention by correcting lysosomal proteolytic deficits. / Yang, Dun Sheng; Stavrides, Philip; Saito, Mitsuo; Kumar, Asok; Rodriguez-Navarro, Jose A.; Pawlik, Monika; Huo, Chunfeng; Walkley, Steven U.; Saito, Mariko; Cuervo, Ana Maria; Nixon, Ralph A.

In: Brain, Vol. 137, No. 12, 01.12.2014, p. 3300-3318.

Research output: Contribution to journalArticle

Yang, DS, Stavrides, P, Saito, M, Kumar, A, Rodriguez-Navarro, JA, Pawlik, M, Huo, C, Walkley, SU, Saito, M, Cuervo, AM & Nixon, RA 2014, 'Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: Prevention by correcting lysosomal proteolytic deficits', Brain, vol. 137, no. 12, pp. 3300-3318. https://doi.org/10.1093/brain/awu278
Yang, Dun Sheng ; Stavrides, Philip ; Saito, Mitsuo ; Kumar, Asok ; Rodriguez-Navarro, Jose A. ; Pawlik, Monika ; Huo, Chunfeng ; Walkley, Steven U. ; Saito, Mariko ; Cuervo, Ana Maria ; Nixon, Ralph A. / Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model : Prevention by correcting lysosomal proteolytic deficits. In: Brain. 2014 ; Vol. 137, No. 12. pp. 3300-3318.
@article{4870c719e84143e7be3c46aaeeb37c99,
title = "Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: Prevention by correcting lysosomal proteolytic deficits",
abstract = "Autophagy, the major lysosomal pathway for the turnover of intracellular organelles is markedly impaired in neurons in Alzheimer's disease and Alzheimer mouse models. We have previously reported that severe lysosomal and amyloid neuropathology and associated cognitive deficits in the TgCRND8 Alzheimer mouse model can be ameliorated by restoring lysosomal proteolytic capacity and autophagy flux via genetic deletion of the lysosomal protease inhibitor, cystatin B. Here we present evidence that macroautophagy is a significant pathway for lipid turnover, which is defective in TgCRND8 brain where lipids accumulate as membranous structures and lipid droplets within giant neuronal autolysosomes. Levels of multiple lipid species including several sphingolipids (ceramide, ganglioside GM3, GM2, GM1, GD3 and GD1a), cardiolipin, cholesterol and cholesteryl esters are elevated in autophagic vacuole fractions and lysosomes isolated from TgCRND8 brain. Lipids are localized in autophagosomes and autolysosomes by double immunofluorescence analyses in wild-type mice and colocalization is increased in TgCRND8 mice where abnormally abundant GM2 ganglioside-positive granules are detected in neuronal lysosomes. Cystatin B deletion in TgCRND8 significantly reduces the number of GM2-positive granules and lowers the levels of GM2 and GM3 in lysosomes, decreases lipofuscin-related autofluorescence, and eliminates giant lipid-containing autolysosomes while increasing numbers of normal-sized autolysosomes/lysosomes with reduced content of undigested components. These findings have identified macroautophagy as a previously unappreciated route for delivering membrane lipids to lysosomes for turnover, a function that has so far been considered to be mediated exclusively through the endocytic pathway, and revealed that autophagic-lysosomal dysfunction in TgCRND8 brain impedes lysosomal turnover of lipids as well as proteins. The amelioration of lipid accumulation in TgCRND8 by removing cystatin B inhibition on lysosomal proteases suggests that enhancing lysosomal proteolysis improves the overall environment of the lysosome and its clearance functions, which may be possibly relevant to a broader range of lysosomal disorders beyond Alzheimer's disease.",
keywords = "Alzheimer's disease, Autophagy, Lipids, Lysosome, TgCRND8",
author = "Yang, {Dun Sheng} and Philip Stavrides and Mitsuo Saito and Asok Kumar and Rodriguez-Navarro, {Jose A.} and Monika Pawlik and Chunfeng Huo and Walkley, {Steven U.} and Mariko Saito and Cuervo, {Ana Maria} and Nixon, {Ralph A.}",
year = "2014",
month = "12",
day = "1",
doi = "10.1093/brain/awu278",
language = "English (US)",
volume = "137",
pages = "3300--3318",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "12",

}

TY - JOUR

T1 - Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model

T2 - Prevention by correcting lysosomal proteolytic deficits

AU - Yang, Dun Sheng

AU - Stavrides, Philip

AU - Saito, Mitsuo

AU - Kumar, Asok

AU - Rodriguez-Navarro, Jose A.

AU - Pawlik, Monika

AU - Huo, Chunfeng

AU - Walkley, Steven U.

AU - Saito, Mariko

AU - Cuervo, Ana Maria

AU - Nixon, Ralph A.

PY - 2014/12/1

Y1 - 2014/12/1

N2 - Autophagy, the major lysosomal pathway for the turnover of intracellular organelles is markedly impaired in neurons in Alzheimer's disease and Alzheimer mouse models. We have previously reported that severe lysosomal and amyloid neuropathology and associated cognitive deficits in the TgCRND8 Alzheimer mouse model can be ameliorated by restoring lysosomal proteolytic capacity and autophagy flux via genetic deletion of the lysosomal protease inhibitor, cystatin B. Here we present evidence that macroautophagy is a significant pathway for lipid turnover, which is defective in TgCRND8 brain where lipids accumulate as membranous structures and lipid droplets within giant neuronal autolysosomes. Levels of multiple lipid species including several sphingolipids (ceramide, ganglioside GM3, GM2, GM1, GD3 and GD1a), cardiolipin, cholesterol and cholesteryl esters are elevated in autophagic vacuole fractions and lysosomes isolated from TgCRND8 brain. Lipids are localized in autophagosomes and autolysosomes by double immunofluorescence analyses in wild-type mice and colocalization is increased in TgCRND8 mice where abnormally abundant GM2 ganglioside-positive granules are detected in neuronal lysosomes. Cystatin B deletion in TgCRND8 significantly reduces the number of GM2-positive granules and lowers the levels of GM2 and GM3 in lysosomes, decreases lipofuscin-related autofluorescence, and eliminates giant lipid-containing autolysosomes while increasing numbers of normal-sized autolysosomes/lysosomes with reduced content of undigested components. These findings have identified macroautophagy as a previously unappreciated route for delivering membrane lipids to lysosomes for turnover, a function that has so far been considered to be mediated exclusively through the endocytic pathway, and revealed that autophagic-lysosomal dysfunction in TgCRND8 brain impedes lysosomal turnover of lipids as well as proteins. The amelioration of lipid accumulation in TgCRND8 by removing cystatin B inhibition on lysosomal proteases suggests that enhancing lysosomal proteolysis improves the overall environment of the lysosome and its clearance functions, which may be possibly relevant to a broader range of lysosomal disorders beyond Alzheimer's disease.

AB - Autophagy, the major lysosomal pathway for the turnover of intracellular organelles is markedly impaired in neurons in Alzheimer's disease and Alzheimer mouse models. We have previously reported that severe lysosomal and amyloid neuropathology and associated cognitive deficits in the TgCRND8 Alzheimer mouse model can be ameliorated by restoring lysosomal proteolytic capacity and autophagy flux via genetic deletion of the lysosomal protease inhibitor, cystatin B. Here we present evidence that macroautophagy is a significant pathway for lipid turnover, which is defective in TgCRND8 brain where lipids accumulate as membranous structures and lipid droplets within giant neuronal autolysosomes. Levels of multiple lipid species including several sphingolipids (ceramide, ganglioside GM3, GM2, GM1, GD3 and GD1a), cardiolipin, cholesterol and cholesteryl esters are elevated in autophagic vacuole fractions and lysosomes isolated from TgCRND8 brain. Lipids are localized in autophagosomes and autolysosomes by double immunofluorescence analyses in wild-type mice and colocalization is increased in TgCRND8 mice where abnormally abundant GM2 ganglioside-positive granules are detected in neuronal lysosomes. Cystatin B deletion in TgCRND8 significantly reduces the number of GM2-positive granules and lowers the levels of GM2 and GM3 in lysosomes, decreases lipofuscin-related autofluorescence, and eliminates giant lipid-containing autolysosomes while increasing numbers of normal-sized autolysosomes/lysosomes with reduced content of undigested components. These findings have identified macroautophagy as a previously unappreciated route for delivering membrane lipids to lysosomes for turnover, a function that has so far been considered to be mediated exclusively through the endocytic pathway, and revealed that autophagic-lysosomal dysfunction in TgCRND8 brain impedes lysosomal turnover of lipids as well as proteins. The amelioration of lipid accumulation in TgCRND8 by removing cystatin B inhibition on lysosomal proteases suggests that enhancing lysosomal proteolysis improves the overall environment of the lysosome and its clearance functions, which may be possibly relevant to a broader range of lysosomal disorders beyond Alzheimer's disease.

KW - Alzheimer's disease

KW - Autophagy

KW - Lipids

KW - Lysosome

KW - TgCRND8

UR - http://www.scopus.com/inward/record.url?scp=84922368172&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922368172&partnerID=8YFLogxK

U2 - 10.1093/brain/awu278

DO - 10.1093/brain/awu278

M3 - Article

C2 - 25270989

AN - SCOPUS:84922368172

VL - 137

SP - 3300

EP - 3318

JO - Brain

JF - Brain

SN - 0006-8950

IS - 12

ER -