ArticleInternational journal of molecular sciences2019
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.
Article in International journal of molecular sciences, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 59 citations in OpenAlex.
- Glial Cysteine Cathepsins: From Homeostasis to Neurodegeneration.Cellular and molecular neurobiology · 2026Review
- Monitoring Lysosomal Viscosity in Hyperglycemia in Association with CaChemical & biomedical imaging · 2026Article
- Exercise-Induced Exerkines Modulate Autophagy: Implications for Interorgan Crosstalk in the Hallmarks of Ageing.International journal of molecular sciences · 2026Review
- Ginseng extract improves synaptic resiliency: A key factor for healthy cognitive aging.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Recombinant cathepsins B and L promote α-synuclein clearance and restore lysosomal function in human and murine models with α-synuclein pathology.Molecular neurodegeneration · 2025Article
- Lysosomal targeting of liposomes with acidic pH and Cathepsin B induces protein aggregate clearance.Cell communication and signaling : CCS · 2025Article
- Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse NaJournal of advanced research · 2025Article
- Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates.Heliyon · 2024Article
- Suppression of the amyloidogenic metabolism of APP and the accumulation of Aβ by alcadein α in the brain during aging.Scientific reports · 2024Article
- Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer's disease.PLoS biology · 2024Article
- Sex differences in response to obesity and caloric restriction on cognition and hippocampal measures of autophagic-lysosomal transcripts and signaling pathways.BMC neuroscience · 2024Article
- Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer's disease and other proteinopathies.Ageing research reviews · 2024Review
- Unlocking the potential of exercise: harnessing myokines to delay musculoskeletal aging and improve cognitive health.Frontiers in physiology · 2024Review
- Golgi defect as a major contributor to lysosomal dysfunction.Frontiers in cell and developmental biology · 2024Review
- Secretase promotes AD progression: simultaneously cleave Notch and APP.Frontiers in aging neuroscience · 2024Review
- The Role of Cysteine Protease Cathepsins B, H, C, and X/Z in Neurodegenerative Diseases and Cancer.International journal of molecular sciences · 2023Review
- Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by TyrScience advances · 2023Article
- Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2023Review
- Pathophysiology of Lysosomes in a Nutshell.International journal of molecular sciences · 2023Article
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
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'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.
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Registered trials
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