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The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment
Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer’s disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Compr...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770842/ https://www.ncbi.nlm.nih.gov/pubmed/31505809 http://dx.doi.org/10.3390/ijms20184432 |
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author | Hwang, Jeannie Estick, Candice M. Ikonne, Uzoma S. Butler, David Pait, Morgan C. Elliott, Lyndsie H. Ruiz, Sarah Smith, Kaitlan Rentschler, Katherine M. Mundell, Cary Almeida, Michael F. Bear, Nicole Stumbling Locklear, James P. Abumohsen, Yara Ivey, Cecily M. Farizatto, Karen L.G. Bahr, Ben A. |
author_facet | Hwang, Jeannie Estick, Candice M. Ikonne, Uzoma S. Butler, David Pait, Morgan C. Elliott, Lyndsie H. Ruiz, Sarah Smith, Kaitlan Rentschler, Katherine M. Mundell, Cary Almeida, Michael F. Bear, Nicole Stumbling Locklear, James P. Abumohsen, Yara Ivey, Cecily M. Farizatto, Karen L.G. Bahr, Ben A. |
author_sort | Hwang, Jeannie |
collection | PubMed |
description | Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer’s disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson’s disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid β 42 (Aβ42) degradation product Aβ38, and this indicator of Aβ42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted Aβ42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing Aβ deposits as well. PADK also reduced amyloidogenic peptides and α-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum. |
format | Online Article Text |
id | pubmed-6770842 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67708422019-10-30 The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment Hwang, Jeannie Estick, Candice M. Ikonne, Uzoma S. Butler, David Pait, Morgan C. Elliott, Lyndsie H. Ruiz, Sarah Smith, Kaitlan Rentschler, Katherine M. Mundell, Cary Almeida, Michael F. Bear, Nicole Stumbling Locklear, James P. Abumohsen, Yara Ivey, Cecily M. Farizatto, Karen L.G. Bahr, Ben A. Int J Mol Sci Article Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer’s disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson’s disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid β 42 (Aβ42) degradation product Aβ38, and this indicator of Aβ42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted Aβ42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing Aβ deposits as well. PADK also reduced amyloidogenic peptides and α-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum. MDPI 2019-09-09 /pmc/articles/PMC6770842/ /pubmed/31505809 http://dx.doi.org/10.3390/ijms20184432 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hwang, Jeannie Estick, Candice M. Ikonne, Uzoma S. Butler, David Pait, Morgan C. Elliott, Lyndsie H. Ruiz, Sarah Smith, Kaitlan Rentschler, Katherine M. Mundell, Cary Almeida, Michael F. Bear, Nicole Stumbling Locklear, James P. Abumohsen, Yara Ivey, Cecily M. Farizatto, Karen L.G. Bahr, Ben A. The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment |
title | The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment |
title_full | The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment |
title_fullStr | The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment |
title_full_unstemmed | The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment |
title_short | The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment |
title_sort | role of lysosomes in a broad disease-modifying approach evaluated across transgenic mouse models of alzheimer’s disease and parkinson’s disease and models of mild cognitive impairment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770842/ https://www.ncbi.nlm.nih.gov/pubmed/31505809 http://dx.doi.org/10.3390/ijms20184432 |
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