| 1. |
- Armstrong, Andrea, et al.
(författare)
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Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
- 2014
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Ingår i: Neuromolecular medicine. - : Humana Press. - 1535-1084 .- 1559-1174. ; 16:1, s. 150-160
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Tidskriftsartikel (refereegranskat)abstract
- The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.
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| 2. |
- Rosen, Christoffer, et al.
(författare)
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Cerebrospinal Fluid Profiles of Amyloid beta-Related Biomarkers in Alzheimers Disease
- 2012
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Ingår i: Neuromolecular medicine. - : Humana Press (Springer Imprint). - 1535-1084 .- 1559-1174. ; 14:1, s. 65-73
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Tidskriftsartikel (refereegranskat)abstract
- The amyloid cascade hypothesis on the pathogenesis of Alzheimers disease (AD) states that amyloid beta (A beta) accumulation in the brain is a key factor that initiates the neurodegenerative process. A beta is generated from amyloid precursor protein (APP) through sequential cleavages by BACE1 (the major beta-secretase in the brain) and gamma-secretase. The purpose of this study was to characterize APP metabolism in vivo in AD patients versus cognitively healthy subjects by examining alterations in cerebrospinal fluid (CSF) biomarkers. We measured BACE1 activity and concentrations of alpha- and beta-cleaved soluble APP (sAPP alpha and sAPP beta, respectively) and A beta 40 in CSF, biomarkers that all reflect the metabolism of APP, in 75 AD patients and 65 cognitively healthy controls. These analytes were also applied in a multivariate model to determine whether they provided any added diagnostic value to the core CSF AD biomarkers A beta 42, T-tau, and P-tau. We found no significant differences in BACE1 activity or sAPP alpha, sAPP beta, and A beta 40 concentrations between AD patients and controls. A multivariate model created with all analytes did not improve the separation of AD patients from controls compared with using the core AD biomarkers alone, highlighting the strong diagnostic performance of A beta 42, T-tau, and P-tau for AD. However, AD patients in advanced clinical stage, as determined by low MMSE score (a parts per thousand currency sign20), had lower BACE1 activity and sAPP alpha, sAPP beta, and A beta 40 concentrations than patients with higher MMSE score, suggesting that these markers may be related to the severity of the disease.
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