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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
- Source :
- International Journal of Molecular Sciences, Vol 20, Iss 18, p 4432 (2019), International Journal of Molecular Sciences, Volume 20, Issue 18
- Publication Year :
- 2019
- Publisher :
- MDPI AG, 2019.
-
Abstract
- Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer&rsquo<br />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&rsquo<br />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 &beta<br />42 (A&beta<br />42) degradation product A&beta<br />38, and this indicator of A&beta<br />42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK<br />also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted A&beta<br />42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing A&beta<br />deposits as well. PADK also reduced amyloidogenic peptides and &alpha<br />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.
- Subjects :
- Parkinson's disease
Z-Phe-Ala-CHN2
cathepsin B
Cathepsin B
lcsh:Chemistry
Mice
0302 clinical medicine
Amyloid precursor protein
lcsh:QH301-705.5
Spectroscopy
Neurons
0303 health sciences
biology
LAMP1
ZFAD
Aβ42
Brain
Parkinson Disease
General Medicine
Computer Science Applications
PADK
Genetically modified mouse
Mice, Transgenic
Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
α-synuclein
Downregulation and upregulation
Alzheimer Disease
mental disorders
medicine
Animals
Humans
Dementia
Cognitive Dysfunction
Physical and Theoretical Chemistry
Molecular Biology
030304 developmental biology
Amyloid beta-Peptides
Organic Chemistry
Lysosome-Associated Membrane Glycoproteins
Colocalization
medicine.disease
synaptic repair
Peptide Fragments
age
lcsh:Biology (General)
lcsh:QD1-999
Synapses
biology.protein
Lysosomes
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 20
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....40c4e747618585efd583ce2ce5ea3697