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.

Autor:	Hwang J; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT 06269, USA., Estick CM; Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT 06269, USA.; Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA., Ikonne US; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Butler D; Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT 06269, USA.; Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA., Pait MC; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Chemistry and Physics, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Elliott LH; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Biology, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Ruiz S; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Biology, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Smith K; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Molecular Biotechnology Program University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Rentschler KM; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Mundell C; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Biology, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Almeida MF; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Stumbling Bear N; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Biology, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Locklear JP; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Biology, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Abumohsen Y; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Biology, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Ivey CM; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Biology, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Farizatto KLG; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA.; Department of Biology, University of North Carolina-Pembroke, Pembroke, NC 28372, USA., Bahr BA; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA. bahr@uncp.edu.; Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT 06269, USA. bahr@uncp.edu.; Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA. bahr@uncp.edu.; Department of Chemistry and Physics, University of North Carolina-Pembroke, Pembroke, NC 28372, USA. bahr@uncp.edu.; Department of Biology, University of North Carolina-Pembroke, Pembroke, NC 28372, USA. bahr@uncp.edu.; Molecular Biotechnology Program University of North Carolina-Pembroke, Pembroke, NC 28372, USA. bahr@uncp.edu.
Jazyk:	angličtina
Zdroj:	International journal of molecular sciences [Int J Mol Sci] 2019 Sep 09; Vol. 20 (18). Date of Electronic Publication: 2019 Sep 09.
DOI:	10.3390/ijms20184432
Abstrakt:	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.
Databáze:	MEDLINE
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