Journal of Alzheimer's Disease - Volume 65, issue 1

Authors: Qin, Yiren | Zhang, Yu | Tomic, Inge | Hao, Wenlin | Menger, Michael D. | Liu, Chunfeng | Fassbender, Klaus | Liu, Yang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-β (Aβ ) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aβ and p-Tau are two major pathogenic molecules with tau acting downstream to Aβ to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb …761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3β . Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes. Show more

Keywords: Alzheimer’s disease, autophagy, Ginkgo biloba extract, inflammation, tauopathies

DOI: 10.3233/JAD-180426

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 243-263, 2018

Authors: Vandermeeren, Marc | Borgers, Marianne | Van Kolen, Kristof | Theunis, Clara | Vasconcelos, Bruno | Bottelbergs, Astrid | Wintmolders, Cindy | Daneels, Guy | Willems, Roland | Dockx, Koen | Delbroek, Lore | Marreiro, André | Ver Donck, Luc | Sousa, Cristiano | Nanjunda, Rupesh | Lacy, Eilyn | Van De Casteele, Tom | Van Dam, Debby | De Deyn, Peter Paul | Kemp, John A. | Malia, Thomas J. | Mercken, Marc H.

Article Type: Research Article

Abstract: The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer’s disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we …describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstrated to be isoform-selective (PT18 and hTau56) or phospho-selective (PT84). Evaluation of the antibodies in cellular- and in vivo seeding assays revealed clear differences in maximal efficacy. Limited proteolysis experiments support the hypothesis that some epitopes are more exposed than others in the tau seeds. Moreover, antibody efficacy seems to depend on the structural properties of fibrils purified from tau Tg mice- and postmortem human AD brain. Show more

Keywords: Epitope mapping, immunotherapy, in vivo seeding, tau antibodies

DOI: 10.3233/JAD-180404

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 265-281, 2018

Authors: Mercorio, Roberta | Pergoli, Laura | Galimberti, Daniela | Favero, Chiara | Carugno, Michele | Dalla Valle, Elisabetta | Barretta, Francesco | Cortini, Francesca | Scarpini, Elio | Valentina, Valentina Bollati | Pesatori, Angela Cecilia

Article Type: Research Article

Abstract: Epigenetic mechanisms might be involved in Alzheimer’s disease (AD). Genetic polymorphisms in several genes, including APOE (Apolipoprotein E), PSEN1 (Presenilin 1), CR1 (Complement receptor 1), and PICALM (Phosphatidylinositol binding clathrin assembly protein), have been associated to an increased AD risk. However, data regarding methylation of these specific genes are lacking. We evaluated DNA methylation measured by quantitative bisulfite-PCR pyrosequencing in 43 AD patients and 38 healthy subjects (HS). In a multivariate age- and gender-adjusted model, PICALM methylation was decreased in AD compared to HS (mean = 3.54 and 4.63, respectively, p = 0.007). In …AD, PICALM methylation level was also positively associated to Mini-Mental Scale Examination (MMSE) score (percent change 3.48%, p = 0.008). Moreover, a negative association between PICALM methylation and age was observed only in HS (percent change – 2.29%, p = 0.002). In conclusion, our data suggest a possible role of PICALM methylation in AD, particularly related to cognitive function. Given the small study sample and the associative nature of our study, further prospective investigations are required to assess the dynamics of DNA methylation in the early stages of AD development. Show more

Keywords: Alzheimer’s disease, epigenetics, methylation, Mini-Mental State Examination, PICALM

DOI: 10.3233/JAD-180242

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 283-292, 2018

Authors: Scott, Tammy M. | Bhadelia, Rafeeque A. | Qiu, Wei Qiao | Folstein, Marshal F. | Rosenberg, Irwin H.

Article Type: Research Article

Abstract: Background: There is evidence that Alzheimer’s disease (AD) has significant cerebrovascular etiopathogenesis. Understanding potentially modifiable risk factors for vascular disease can help design long-term intervention strategies for controlling or preventing cognitive dysfunction attributable to cerebrovascular disease. Objective: To evaluate the presence and severity of markers of cerebrovascular pathology, its relationship to diagnostic categories of dementia, including AD, and association with the metabolic biomarker homocysteine. Methods: In a cross-sectional observational study, 340 community-dwelling elders received a clinical evaluation including brain MRI and neuropsychological tests. Dementia and mild cognitive impairment (MCI) were diagnosed by consensus committee. Fasting total …plasma homocysteine was measured. Statistical analyses were adjusted for demographics and cerebrovascular risk factors. Results: Nearly 25% of those diagnosed with AD had small vessel infarcts (SVI). Periventricular white matter hyperintensity (pvWMHI) was prevalent in participants with AD (61%) or MCI (amnesic 61% and non-amnesic 54%, respectively). Participants with SVI and/or pvWMHI also had greater brain atrophy. Homocysteine concentrations were higher in individuals with cerebrovascular findings than in those without. In individuals with cerebrovascular disease, homocysteine was inversely related to executive function (p = 0.022) and directly related to degree of brain atrophy (p = 0.009). Conclusions: We demonstrated a significant prevalence of small vessel markers of cerebrovascular pathology in individuals diagnosed with AD, with a significant concurrence between cerebrovascular disease and brain and ventricular atrophy. While current research on AD has focused on amyloid-βpeptide deposition, tau-pathology, and microglial activation and inflammation, greater attention to the cerebrovascular contribution to this neurodegenerative disease presents an additional target for therapeutic prevention and intervention. Show more

Keywords: Aging, Alzheimer’s disease, cerebrovascular disease, dementia, homocysteine, magnetic resonance imaging, neuropsychological testing, small vessel pathology

DOI: 10.3233/JAD-180366

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 293-302, 2018

Authors: Ali, Jordan I. | Smart, Colette M. | Gawryluk, Jodie R.

Article Type: Research Article

Abstract: Individuals with subjective cognitive decline (SCD) report self-perceived declines in cognitive function but perform within normal limits on standardized tests. However, for some, these self-perceived changes may herald eventual decline to Alzheimer’s disease (AD). In light of this, the relationship between SCD and APOE ɛ 4, a known genetic risk factor for AD, has garnered interest; however, no systematic review of this literature exists. The current review (n = 36 articles) examined the prevalence of APOE ɛ 4 in SCD samples relative to healthy and objectively impaired samples, and summarized APOE ɛ 4-related risk of conversion from SCD to …AD. Univariate ANOVA indicated that APOE ɛ 4 frequency was comparable between healthy control and SCD samples, yet significantly higher in objectively impaired samples (i.e., MCI, AD) relative to either of these groups. Narrative review provided mixed evidence linking coincident APOE ɛ 4-positive genotype and SCD to structural neuropathology. Though there was little evidence to suggest that APOE ɛ 4 predisposes individuals to developing SCD, both APOE ɛ 4 and SCD were found to confer individual and multiplicative risk of conversion to objective cognitive impairment. Combined, it is likely that a relationship between APOE ɛ 4, SCD, and AD exists, though its exact nature remains undetermined. A clearer understanding of these relationships is hindered by a lack of standardization in SCD classification and a dearth of longitudinal outcome research. Wide-scale adoption of genetic screening for dementia risk in persons with SCD is considered premature at this time. Ethical considerations and clinical implications of genetic testing for dementia risk are discussed. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E4, cognitive dysfunction, dementia, diagnostic self evaluation, prodromal symptoms, review

DOI: 10.3233/JAD-180248

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 303-320, 2018