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      A Comparison of Lysosomal Enzymes Expression Levels in Peripheral Blood of Mild- and Severe-Alzheimer’s Disease and MCI Patients: Implications for Regenerative Medicine Approaches

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          Abstract

          The association of lysosomal dysfunction and neurodegeneration has been documented in several neurodegenerative diseases, including Alzheimer’s Disease (AD). Herein, we investigate the association of lysosomal enzymes with AD at different stages of progression of the disease (mild and severe) or with mild cognitive impairment (MCI). We conducted a screening of two classes of lysosomal enzymes: glycohydrolases (β-Hexosaminidase, β-Galctosidase, β-Galactosylcerebrosidase, β-Glucuronidase) and proteases (Cathepsins S, D, B, L) in peripheral blood samples (blood plasma and PBMCs) from mild AD, severe AD, MCI and healthy control subjects. We confirmed the lysosomal dysfunction in severe AD patients and added new findings enhancing the association of abnormal levels of specific lysosomal enzymes with the mild AD or severe AD, and highlighting the difference of AD from MCI. Herein, we showed for the first time the specific alteration of β-Galctosidase (Gal), β-Galactosylcerebrosidase (GALC) in MCI patients. It is notable that in above peripheral biological samples the lysosomes are more sensitive to AD cellular metabolic alteration when compared to levels of Aβ-peptide or Tau proteins, similar in both AD groups analyzed. Collectively, our findings support the role of lysosomal enzymes as potential peripheral molecules that vary with the progression of AD, and make them useful for monitoring regenerative medicine approaches for AD.

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          Most cited references46

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          Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type.

          J Morris (1997)
          Global staging measures for dementia of the Alzheimer type (DAT) assess the influence of cognitive loss on the ability to conduct everyday activities and represent the "ultimate test" of efficacy for antidementia drug trials. They provide information about clinically meaningful function and behavior and are less affected by the "floor" and "ceiling" effects commonly associated with psychometric tests. The Washington University Clinical Dementia Rating (CDR) is a global scale developed to clinically denote the presence of DAT and stage its severity. The clinical protocol incorporates semistructured interviews with the patient and informant to obtain information necessary to rate the subject's cognitive performance in six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The CDR has been standardized for multicenter use, including the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and the Alzheimer's Disease Cooperative Study, and interrater reliability has been established. Criterion validity for both the global CDR and scores on individual domains has been demonstrated, and the CDR also has been validated neuropathologically, particularly for the presence or absence of dementia. Standardized training protocols are available. Although not well suited as a brief screening tool for population surveys of dementia because the protocol depends on sufficient time to conduct interviews, the CDR has become widely accepted in the clinical setting as a reliable and valid global assessment measure for DAT.
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            Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques.

            Through a comprehensive analysis of organellar markers in mouse models of Alzheimer's disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer's disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer's disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.
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              Cerebrospinal Fluid Lysosomal Enzymes and Alpha-Synuclein in Parkinson's Disease

              To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinson's disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of β-glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric α-synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of β-glucocerebrosidase, β-mannosidase, β-hexosaminidase, and β-galactosidase were measured with established enzymatic assays, while α-synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n = 44) was also screened for mutations in the β-glucocerebrosidase-encoding gene (GBA1). In the PD group, β-glucocerebrosidase activity was reduced (P < 0.05) and patients at earlier stages showed lower enzymatic activity (P < 0.05); conversely, β-hexosaminidase activity was significantly increased (P < 0.05). Eight PD patients (18%) presented GBA1 sequence variations; 3 of them were heterozygous for the N370S mutation. Levels of total α-synuclein were significantly reduced (P < 0.05) in PD, in contrast to increased levels of α-synuclein oligomers, with a higher oligomeric/total α-synuclein ratio in PD patients when compared with controls (P < 0.001). A combination of β-glucocerebrosidase activity, oligomeric/total α-synuclein ratio, and age gave the best performance in discriminating PD from neurological controls (sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve = 0.87). These results demonstrate the possibility of detecting lysosomal dysfunction in CSF and further support the need to combine different biomarkers for improving the diagnostic accuracy of PD.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                19 August 2017
                August 2017
                : 18
                : 8
                : 1806
                Affiliations
                [1 ]Department of Chemistry, Biology and Biotechnology, Biochemistry and Molecular Biology Unit, University of Perugia, Perugia 06123, Italy; effemorena@ 123456gmail.com (F.M.); chiara.argentati89@ 123456gmail.com (C.A.); rosa.trotta@ 123456tiscali.it (R.T.); carla.emiliani@ 123456unipg.it (C.E.)
                [2 ]Department of Surgery and Biomedical Sciences, Section of Human, Clinical and Forensic Anatomy, School of Medicine, University of Perugia, Perugia 06132, Italy; lucia.crispoltoni@ 123456gmail.com (L.C.); anna.stabile@ 123456unipg.it (A.S.); alessandra.pistilli@ 123456unipg.it (A.P.); mario.rende@ 123456unipg.it (M.R.)
                [3 ]Department of Aging Medical Science, University of G. d’Annunzio, Chieti e Pescara, Chieti 66100, Italy; a.dibaldassarre@ 123456unich.it
                [4 ]Department of Medicine, Section of Cardiovascular, Endocrine and Metabolic Clinical Physiology and Laboratory for Endocrine Cell Transplants and Bio-hybrid Organs, University of Perugia, Perugia 06132, Italy; riccardo.calafiore@ 123456unipg.it (R.C.); piamontanucci@ 123456hotmail.com (P.M.); gius.basta@ 123456gmail.com (G.B.)
                [5 ]Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona 37134, Italy; anna.pedrinolla@ 123456univr.it (A.P.); nicola.smania@ 123456univr.it (N.S.); massimo.venturelli@ 123456univr.it (M.V.); federico.schena@ 123456univr.it (F.S.)
                [6 ]Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Roma, Roma 06100, Italy; fabio.naro@ 123456uniroma1.it
                Author notes
                [* ]Correspondence: sabata.martino@ 123456unipg.it ; Tel.: +39-07-5585-7442; Fax: +39-07-5585-7443
                Article
                ijms-18-01806
                10.3390/ijms18081806
                5578193
                28825628
                35742c3d-444f-4bf6-902b-3318315f7263
                © 2017 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/).

                History
                : 07 July 2017
                : 14 August 2017
                Categories
                Article

                Molecular biology
                β-hexosaminidase,β-galactosidase,β-galactosylcebrosidase,β-glucuronidase,cathepsin s,cathepsin d,cathepsin b,cathepsin l,dementia,neurodegeneration,aging

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