scholarly journals 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

2019 ◽  
Vol 20 (18) ◽  
pp. 4432 ◽  
Author(s):  
Jeannie Hwang ◽  
Candice M. Estick ◽  
Uzoma S. Ikonne ◽  
David Butler ◽  
Morgan C. Pait ◽  
...  

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.

2019 ◽  
Vol 34 (8) ◽  
pp. 1244-1250 ◽  
Author(s):  
Eleanor King ◽  
John O'Brien ◽  
Paul Donaghy ◽  
Caroline H. Williams-Gray ◽  
Rachael A. Lawson ◽  
...  

2017 ◽  
Vol 13 (7S_Part_8) ◽  
pp. P416-P416
Author(s):  
Ting Ting Yong ◽  
Russell J. Chander ◽  
Heidi Emmanuel Foo ◽  
Levinia Lim ◽  
Aloysius Yue Tat Ng ◽  
...  

2015 ◽  
Vol 29 (3) ◽  
pp. 112-119 ◽  
Author(s):  
Johann Lehrner ◽  
Harald Krakhofer ◽  
Claus Lamm ◽  
Stefan Macher ◽  
Doris Moser ◽  
...  

Brain ◽  
2020 ◽  
Vol 143 (3) ◽  
pp. 932-943 ◽  
Author(s):  
Edward N Wilson ◽  
Michelle S Swarovski ◽  
Patricia Linortner ◽  
Marian Shahid ◽  
Abigail J Zuckerman ◽  
...  

Abstract Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease and affects 1% of the population above 60 years old. Although Parkinson’s disease commonly manifests with motor symptoms, a majority of patients with Parkinson’s disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson’s disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer’s disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson’s disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer’s disease. Given the known association of microglial activation with advancing Parkinson’s disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson’s disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson’s disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson’s disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson’s disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson’s disease.


2016 ◽  
Vol 27 ◽  
pp. 54-60 ◽  
Author(s):  
Lilah M. Besser ◽  
Irene Litvan ◽  
Sarah E. Monsell ◽  
Charles Mock ◽  
Sandra Weintraub ◽  
...  

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