Journal of Alzheimer's Disease - Volume 73, issue 1

Authors: Francis, Nikita | Robison, Lisa S. | Popescu, Dominique L. | Michaelos, Michalis | Hatfield, Joshua | Xu, Feng | Zhu, Xiaoyue | Davis, Judianne | Anderson, Maria E. | Anderson, Brenda J. | Van Nostrand, William E. | Robinson, John K.

Article Type: Research Article

Abstract: Exercise has been shown to be protective against the risk of dementias, including Alzheimer’s disease (AD). Intervention studies have demonstrated its ability to mitigate cognitive and behavioral impairments and reduce disease in both humans and animals. However, information is lacking in regard to the volume and intensity, as well as timing of exercise onset with respect to disease stage, which produces optimal benefits. Here, utilizing the Tg2576 mouse, a model of AD-like parenchymal amyloid pathology and cognitive impairment, we sought to understand the effects of different lengths of daily access to a running wheel on advanced stage disease. This study …is the first to determine the benefits of long-term exercise (4 months of voluntary running) and different periods of daily access to a running wheel (0 h, 1 h, 3 h, and 12 h running wheel access) beginning in 14-month-old Tg2576 mice, an age with significant amyloid pathology. We found that exercising Tg2576 animals showed lower levels of some aspects of AD pathology and reduced behavioral dysfunction compared to sedentary Tg2576 animals. High intensity exercise, rather than high volume exercise, was generally most beneficial in reducing amyloid pathology. Our results suggest that engaging in vigorous exercise programs, even after living a sedentary life, may lead to a measurable reduction in AD pathology and preservation of some cognitive abilities. Show more

Keywords: Amyloid, behavior, dementia, exercise, transgenic

DOI: 10.3233/JAD-190810

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 359-374, 2020

Authors: Song, Shasha | Chen, Jingjiong | Xiao, Pinpin | Duan, Hao | Zhou, Yajun | Wang, Feng | Wang, Hongmei | Zhao, Yuwu | Geng, Zhi

Article Type: Research Article

Abstract: Continuous epileptic seizures hallmark status epilepticus, leading to preferential neuronal cell loss in the hippocampus that can progress into Alzheimer’s disease. Previous studies have shown that status epilepticus prompts an overproduction of nitric oxide (NO) by upregulation of NO synthase II (NOS II) to induce apoptosis of neuronal cells in the hippocampus, in a nuclear factor-kappaB (NF-κ B) signaling dependent manner. Here, in an experimental rat model for status epilepticus, elicitation of sustained seizure activity was achieved by microinjection of kainic acid (KA) into the hippocampal CA3 subfield. We found that KA induced features of status epilepticus, which could be …attenuated by blocking NF-κ B signaling through a specific inhibitor. Interestingly, infiltration of macrophages of primarily pro-inflammatory subtype was detected in the hippocampal CA3 region immediately after KA injection. Experimental elimination of macrophages by an anti-CD115 antibody significantly attenuated the features of status epilepticus, likely through suppressing activation of NF-κ B signaling. Together, these data suggest that macrophages play a critical role in NF-κ B signaling-mediated status epilepticus that predisposes to Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, kainic acid, macrophages, NF-κB, status epilepticus

DOI: 10.3233/JAD-190994

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 375-382, 2020

Authors: Wada-Isoe, Kenji | Kikuchi, Takashi | Umeda-Kameyama, Yumi | Mori, Takahiro | Akishita, Masahiro | Nakamura, Yu | on behalf of the ABC Dementia Scale Research Group

Article Type: Research Article

Abstract: The course of Alzheimer’s disease (AD) varies between individuals, and the relationship between cognitive and functional decline and the deterioration of behavioral and psychological symptoms of dementia (BPSD) is still poorly understood. Until recently, it was challenging to monitor subsequent changes in these symptoms because there was no single composite scale available that could simultaneously evaluate activities of daily living (ADL), BPSD, and cognitive function (CF) states. The present authors developed a new, brief assessment scale, the “ABC Dementia Scale” (ABC-DS), which is based on item response theory and facilitates concurrent measurement of ADL, BPSD, and CF states. We previously …presented the reliability, construct validity, concurrent validity, and responsiveness of the ABC-DS. We obtained the evidence through three clinical trials featuring 1,400 subjects in total. In the present study, we performed a secondary analysis of the data obtained in the previous study. We conducted hierarchical cluster analyses that allowed us to classify 197 AD patients in terms of similarities regarding ADL, BPSD, and CF domain scores, as measured by the ABC-DS. Consequently, the scale identified subgroups of patients with global clinical dementia ratings of 1, 2, and 3. Considering our results in conjunction with the clinical experiences of the AD expert among the present authors regarding longitudinal changes in ADL, BPSD, and CF, we were able to propose potential progression pathways of AD in the form of a hypothetical roadmap. Show more

Keywords: ABC dementia scale, activities of daily living, Alzheimer’s disease, cognitive function, cluster analysis, psychological symptoms of dementia

DOI: 10.3233/JAD-190767

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 383-392, 2020

Authors: Bastrup, Joakim | Kastaniegaard, Kenneth | Asuni, Ayodeji A. | Volbracht, Christiane | Stensballe, Allan

Article Type: Research Article

Abstract: Amyloid plaques are one of the hallmarks of Alzheimer’s disease (AD). The main constituent of amyloid plaques is amyloid-β peptides, but a complex interplay of other infiltrating proteins also co-localizes. We hypothesized that proteomic analysis could reveal differences between amyloid plaques and adjacent control tissue in the transgenic mouse model of AD (APPPS1-21) and in similar regions from non-transgenic littermates. Our microproteomic strategy included isolation of regions of interest by laser capture microdissection and analysis by liquid chromatography mass spectrometry-based label-free relative quantification. We consistently identified 183, 224, and 307 proteins from amyloid plaques, adjacent control and non-tg samples, respectively. …Pathway analysis revealed 27 proteins that were significantly regulated when comparing amyloid plaques and corresponding adjacent control regions. We further elucidated that co-localized proteins were subjected to post-translational modifications and are the first to report 193 and 117 unique modifications associated to amyloid plaques and adjacent control extracts, respectively. The three most common modifications detected in proteins from the amyloid plaques were oxidation, deamidation, and pyroglutamylation. Together, our data provide novel information about the biological processes occurring within and around amyloid plaques in the APPPS1-21 mouse model of AD. Show more

Keywords: Alzheimer’s disease, amyloid plaque, mass spectrometry, microdissection, pyroglutamate

DOI: 10.3233/JAD-190652

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 393-411, 2020

Authors: Kuroda, Eriko | Takata, Kazuyuki | Nishimura, Kaneyasu | Oka, Hikaru | Sueyoshi, Mari | Aitani, Mayu | Kouda, Atsushi | Satake, Shiho | Shima, Chiaki | Toda, Yuki | Nakata, Susumu | Kitamura, Yoshihisa | Ashihara, Eishi

Article Type: Research Article

Abstract: Amyloid-β (Aβ) accumulation in the brain triggers the onset of Alzheimer’s disease (AD), and its prevention and elimination are high priorities for anti-AD therapeutic strategies. Microglia, the resident immune cells in the brain, promote Aβ clearance by phagocytosis. Previously, we demonstrated that injection of primary cultured rat microglia and mouse bone marrow-derived microglia-like cells into the brain decreases the level of Aβ and that intrahippocampal injection of these cells ameliorates cognitive impairment in a mouse model of AD. To advance this cell therapeutic strategy to the clinical stage, less invasive ways of preparing autologous microglia-like cells from elderly patients are …required. In this study, we demonstrated that hematopoietic stem cells mobilized from the bone marrow to peripheral blood by administering granulocyte colony-stimulating factor and a CXCR4 antagonist to mice differentiated into microglia-like cells upon stimulation with colony-stimulating factor 1 and interleukin-34. The peripheral blood-derived microglia-like (PBDML) cells expressed microglial markers and engaged in Aβ phagocytosis. Although PBDML cells were in an anti-inflammatory state under nonstimulated conditions, they expressed mRNAs encoding proinflammatory cytokines following lipopolysaccharide treatment. PBDML cells injected into the hippocampi of a mouse AD model survived for at least 36 days while phagocytosing Aβ, contributed to a reduction in brain Aβ burden, and ameliorated cognitive impairment in the mice. These results strongly suggest that PBDML cells are a promising source for the development of a novel cell therapy against AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , cell therapy, cognitive impairment, intrahippocampal injection, microglia, Morris water maze, novel object recognition test, peripheral blood, stereology

DOI: 10.3233/JAD-190974

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 413-429, 2020