Journal of Alzheimer's Disease - Volume 66, issue 3

Authors: Tuna, Gamze | Yener, Görsev Gülmen | Oktay, Gülgün | İşlekel, Gül Hüray | Kİrkalİ, Fatoş Güldal

Article Type: Research Article

Abstract: Matrix metalloproteinases (MMPs) are substantial regulators of learning and memory and might be involved in neurodegeneration. It is known that MMPs are involved in pathogenesis of Alzheimer’s disease (AD) and are particularly involved in the amyloid-β processing pathway. However, information on circulating levels of these proteins and their tissue inhibitors (TIMPs) in AD and other neurodegenerative dementia (ND) diseases such as dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) is not clear. Therefore, this study was directed toward finding out how plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 vary in AD, DLB, and FTD; and investigating the …correlation of the levels of MMPs and their inhibitors with clinical parameters of the patients. MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were measured by enzyme linked immunosorbent assay (ELISA). Plasma MMP-2 levels were significantly lower in all the patient groups than in the age-matched healthy controls (HCs) (p  < 0.05). MMP-9 levels were significantly lower in the FTD patients than in the HCs (p  < 0.05). Also, TIMP-1 levels were lower in the AD and FTD patients than in the HCs (p  < 0.05). TIMP-2 levels were similar in all the groups. These findings highlight the importance of circulating MMPs in ND and suggest that MMPs and their inhibitors might play a role in impaired amyloid-β peptide metabolism which is responsible for the genesis and progression of ND. Furthermore, measurement of MMP-2 and MMP-9 and their inhibitors may be of great importance for large scale basic research and clinical studies of ND. Show more

Keywords: ELISA, matrix metalloproteinases, neurodegenerative dementia, tissue inhibitor of metalloproteinases

DOI: 10.3233/JAD-180752

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1265-1273, 2018

Authors: Peloso, Gina M. | Beiser, Alexa S. | Destefano, Anita L. | Seshadri, Sudha

Article Type: Research Article

Abstract: Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer’s disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40–60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as …well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p  = 0.006), but no interaction of the GRS with HDL-C (p  = 0.458) or LDL-C (p  = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p -value < 0.05 (rs11218343 and APOE ɛ 4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings. Show more

Keywords: Alzheimer’s disease, association studies in genetics, cohort studies, risk factors in epidemiology

DOI: 10.3233/JAD-180751

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1275-1282, 2018

Authors: van Rooden, Sanneke | van den Berg-Huysmans, Annette A. | Croll, Pauline H. | Labadie, Gerda | Hayes, Jessica M. | Viviano, Raymond | van der Grond, Jeroen | Rombouts, Serge A.R.B. | Damoiseaux, Jessica S.

Article Type: Research Article

Abstract: Background: Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer’s disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD. Objective: The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume). Methods: …67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints. Results: We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD. Conclusion: SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD. Show more

Keywords: Alzheimer’s disease, cerebral small vessel disease, magnetic resonance imaging, subjective cognitive decline

DOI: 10.3233/JAD-180285

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1283-1294, 2018

Authors: Deane, Catherine A.S. | Brown, Ian R.

Article Type: Research Article

Abstract: HSPA6 (Hsp70B’) is an inducible member of the Hsp70 (HSPA) family of heat shock proteins that is present in the human genome and not found in mouse and rat. Hence it is lacking in current animal models of neurodegenerative diseases. To advance knowledge of the little studied HSPA6, differentiated human neuronal SH-SY5Y cells were treated with the proteotoxic stress-inducing agent MG132. A robust induction of HSPA6 was apparent which localized to the periphery of MG132-induced protein aggregates in the neuronal cytoplasm. Components of the protein disaggregation/refolding machine that co-operate with Hsp70 also targeted the periphery of cytoplasmic protein aggregates, including …DNAJB1 (Hsp40–1), HSPH1 (Hsp105α ), and HSPB1 (Hsp27). These data suggest that HSPA6 is involved in the response of human neuronal cells to proteotoxic stress that is a feature of neurodegenerative diseases which have been characterized as protein misfolding disorders. Constitutively expressed HSPA8 (Hsc70) also localized tothe periphery of cytoplasmic protein aggregates following the treatment of differentiated human neuronal cells with MG132. HSPA8 could provide a rapid response to proteotoxic stress in neuronal cells, circumventing the time required to upregulate inducible Hsps. Show more

Keywords: Heat shock protein (Hsp), HSPA6 (Hsp70B’), HSPA8 (Hsc70), human neuronal SH-SY5Y cells, MG132, protein disaggregation/refolding machine, proteotoxic stress

DOI: 10.3233/JAD-180536

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1295-1308, 2018