Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Wilson, George D. | Wilson, Thomas G. | Hanna, Alaa | Kulchycki, Justin | Buelow, Katie | Pruetz, Barbara L. | Michael, Daniel B. | Chinnaiyan, Prakash | Maddens, Michael E. | Martinez, Alvaro A. | Fontanesi, James

Article Type: Short Communication

Abstract: We have previously reported that low doses of external beam ionizing irradiation reduced amyloid-β (Aβ) plaques and improved cognition in APP/PS1 mice. In this study we investigated the effects of radiation in an age-matched series of 3xTg-AD mice. Mice were hemibrain-irradiated with 5 fractions of 2 Gy and sacrificed 8 weeks after the end of treatment. Aβ and tau were assessed using immunohistochemistry and quantified using image analysis with Definiens Tissue Studio. We observed a significant reduction in Aβ plaque burden and tau staining; these two parameters were significantly correlated. This preliminary data is further support that low doses of radiation …may be beneficial in Alzheimer’s disease. Show more

Keywords: Amyloid-β, radiation, reduction, tau

DOI: 10.3233/JAD-200030

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Li, Naiyan | Wang, Gang | Lu, Huarong

Article Type: Research Article

Abstract: Many cardiovascular disorders are predisposing factors for Alzheimer’s disease (AD), but the effects of early myocardial infarction (MI) on future development of AD are not well determined. Here, we performed MI on two different AD models in mice, APP/PS1 and rTg4510, which mimicked the plaque formation by amyloid-β peptide aggregates (Aβ) and neurofibrillary tangle formation by phosphorylated Tau (pTau), respectively. In both strains, we detected increased deposit of Aβ or formation of pTau, increased loss of neurons, and poorer performance in behavior tests including a Morris water maze test for spatial reference memory and a locomotion test for motor activity …in mice that had received MI, compared to mice that had been sham operated. Moreover, in a cohort of selected patients, we found that patients with previous MI had more chances to develop AD in the future. Together, our data suggest that the chances to develop AD may increase after MI. Show more

Keywords: Key words: Alzheimer’s disease, amyloid-β peptide aggregates, myocardial infarction, phosphorylated tau

DOI: 10.3233/JAD-200068

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Lu, Mei-Hong | Zhao, Xiu-Yun | Xu, De-en | Chen, Ji-Bo | Ji, Wen-Li | Huang, Ze-ping | Pan, Ting-ting | Xue, Lu-Lu | Wang, Fen | Li, Qi-Fa | Zhang, Yue | Wang, Ting-Hua | Yanagawa, Yuchio | Liu, Chun-Feng | Xu, Ru-Xiang | Xia, Yi-Yuan | Li, Shao | Ma, Quan-Hong

Article Type: Research Article

Abstract: Excitatory (E) and inhibitory (I) balance of neural network activity is essential for normal brain function and of particular importance to memory. Disturbance of E/I balance contributes to various neurological disorders. The appearance of neural hyperexcitability in Alzheimer’s disease (AD) is even suggested as one of predictors of accelerated cognitive decline. In this study, we found that GAD67+ , Parvalbumin+ , Calretinin+ , and Neuropeptide Y+ interneurons were progressively lost in the brain of APP/PS1 mice. Transplanted embryonic medial ganglionic eminence derived interneuron progenitors (IPs) survived, migrated, and differentiated into GABAergic interneuron subtypes successfully at 2 months after transplantation. Transplantation …of IPs hippocampally rescued impaired synaptic plasticity and cognitive deficits of APP/PS1 transgenic mice, concomitant with a suppression of neural hyperexcitability, whereas transplantation of IPs failed to attenuate amyloid-β accumulation, neuroinflammation, and synaptic loss of APP/PS1 transgenic mice. These observations indicate that transplantation of IPs improves learning and memory of APP/PS1 transgenic mice via suppressing neural hyperexcitability. This study highlights a causal contribution of GABAergic dysfunction to AD pathogenesis and the potentiality of IP transplantation in AD therapy. Show more

Keywords: Alzheimer’s disease, cell transplantation, GABA, hyperexcitability, interneuron, interneuron progenitor

DOI: 10.3233/JAD-200010

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Beydoun, May A. | Beydoun, Hind A. | Hossain, Sharmin | El-Hajj, Ziad W. | Weiss, Jordan | Zonderman, Alan B.

Article Type: Research Article

Abstract: Microbial agents including periodontal pathogens have recently appeared as important actors in Alzheimer’s disease (AD) pathology. We examined associations of clinical periodontal and bacterial parameters with incident all-cause and AD dementia as well as AD mortality among US middle-aged and older adults. Clinical [Attachment Loss (AL); probing pocket depth (PPD)] and bacterial [pathogen immunoglobulin G (IgG)] periodontal markers were investigated in relation to AD and all-cause dementia incidence and to AD mortality, using data from the third National Health and Nutrition Examination Surveys (NHANES III, 1988–1994) linked longitudinally with National Death Index and Medicare data through January 1, 2014, with …up to 26 years of follow-up. Sex- and age-specific multivariable-adjusted Cox proportional hazards models were conducted. Among those ≥65 years, AD incidence and mortality were consistently associated with PPD, two factors and one cluster comprised of IgG titers against Porphyromonas gingivalis (P. gingivalis ), Prevotella melaninogenica (P. melaninogenica ) and Campylobacter rectus (C. rectus ) among others. Specifically, AD incidence was linked to a composite of C. rectus and P. gingivalis titers (per SD, aHR = 1.22; 95% CI, 1.04–1.43, p  = 0.012), while AD mortality risk was increased with another composite (per SD, aHR = 1.46; 95% CI, 1.09–1.96, p  = 0.017) loading highly on IgG for P. gingivalis , Prevotella intermedia , Prevotella nigrescens , Fusobacterium nucleatum , C. rectus , Streptococcus intermedius , Capnocylophaga Ochracea , and P. melaninogenica . This study provides evidence for an association between periodontal pathogens and AD, which was stronger for older adults. Effectiveness of periodontal pathogen treatment on reducing sequelae of neurodegeneration should be tested in randomized controlled trials. Show more

Keywords: Aging, Alzheimer’s disease, dementia, periodontal pathogens, periodontitis

DOI: 10.3233/JAD-200064

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Musaeus, Christian Sandøe | Gleerup, Helena Sophia | Høgh, Peter | Waldemar, Gunhild | Hasselbalch, Steen Gregers | Simonsen, Anja Hviid

Article Type: Research Article

Abstract: Background: Previous studies have shown an association between disruption of the blood-brain-barrier (BBB) and dementias of different etiologies. The protein concentration of cerebrospinal fluid (CSF) can be used as an indirect measurement for the permeability of the BBB using the CSF/plasma albumin quotient (Q-Alb) or total CSF protein. Objective: In the current study, we wanted to investigate Q-Alb and CSF protein concentration in dementias of different etiologies and the possible confounding factors. Methods: A total of 510 patients and healthy controls were included in the current study. The patients were diagnosed with Alzheimer’s disease (AD), dementia …with Lewy bodies (DLB), vascular dementia (VaD), or frontotemporal dementia (FTD). Results: We found that Q-Alb was significantly different between the groups (p  = 0.002, F  = 3.874). Patients with DLB and VaD showed the largest Q-Alb. Although not significant for CSF total protein, we found the same overall pattern for DLB and VaD. When examining confounding factors, we found a positive association with age and a lower Fazekas score in DLB as compared to VaD. Conclusion: These results suggest that Q-Alb can contribute to our understanding of the pathophysiological mechanisms in DLB, and Q-Alb may serve as a supplementary diagnostic marker. Furthermore, we found a positive association with age, which may be due to differences in vascular co-morbidities. In addition, in patients with DLB, the increased Q-Alb is not due to vascular lesions. Studies are needed to validate the possible diagnostic value of Q-Alb in a larger cohort. Show more

Keywords: albumin, Alzheimer’s disease, cerebrospinal fluid, CSF/plasma albumin quotient, frontotemporal dementia, Lewy body dementia, protein, Q-Alb, vascular dementia

DOI: 10.3233/JAD-200168

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Schedin-Weiss, Sophia | Nilsson, Per | Sandebring-Matton, Anna | Axenhus, Michael | Sekiguchi, Misaki | Saito, Takashi | Winblad, Bengt | Saido, Takaomi | Tjernberg, Lars O.

Article Type: Research Article

Abstract: Background: The 42 amino acids long amyloid-β peptide, Aβ42 , may initiate a cascade of events leading to the severe neurodegeneration observed in Alzheimer’s disease (AD) brain. However, the underlying molecular mechanisms remain to be established. Objective: To find early Aβ42 -induced AD related mechanisms, we performed a brain proteomics time-course study on a novel App knock-in AD mouse model, AppNL -F , expressing high levels of Aβ42 without AβPP overexpression artifacts. Methods: Hippocampus and cortex were analyzed separately by using 18 O-labelling mass spectrometry to reveal alterations in protein levels. Pathway …analysis of proteomics data was used to identify altered biological functions. Immunohistochemistry was used to further investigate a significant key regulatory protein. Results: Around 100 proteins were differently expressed in AppNL -F mice at each time point (3, 6, 9, and 18 months of age) as compared to wild type mice. Strikingly, already at 3 months of age—long before Aβ plaque development and memory impairment—several pathways, including long-term potentiation and synaptic plasticity, were downregulated, and neuritogenesis was increased. Huntingtin (HTT) was identified as an upstream regulator, i.e., a key protein affecting the levels of several proteins. Increased levels of HTT in hippocampus of AppNL -F mice was supported by immunofluorescence microscopy. Conclusion: Notably, the proteome was significantly altered already at 3 months of age, 6 months before the development of plaques. Differentially expressed proteins varied over time, indicating that increased Aβ42 levels initiate a cascade of events that eventually manifests in amyloid depositions, inflammation, and decline in memory. Show more

Keywords: Alzheimer’s disease, amyloid-β, App knock-in mouse model, ingenuity pathway analysis, proteomics

DOI: 10.3233/JAD-200028

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Ou, Ya-Nan | Zhu, Jun-Xia | Hou, Xiao-He | Shen, Xue-Ning | Xu, Wei | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The role of infectious agents in the development of Alzheimer’s disease (AD) has long been debated, however, uncertainties still persist. Objective: We aimed to illuminate the associations between infectious agents and risk of AD comprehensively. Methods: Studies examining the associations between AD and infectious agents were identified through a systematic search of PubMed, Embase, and Cochrane library. A random-effects meta-analysis was conducted. Publication bias was explored using funnel plot. Results: Fifty-one studies were included in the systematic review, of which forty-seven studies with 108,723 participants and 4,039 AD cases were eligible for meta-analysis. …Evidence based on case control studies demonstrated that Chlamydia pneumoniae [odds ratio (OR): 4.39, 95% CI = 1.81–10.67; I2  = 68%)], Human herpes virus-6 (OR: 3.97, 95% CI = 2.04–7.75; I2  = 0%, p  = 0.72), Epstein-Barr virus (OR:1.45, 95% CI = 1.00–2.08; I2  = 0%), Herpes simplex virus-1 (OR:1.34, 95% CI = 1.02–1.75; I2  = 0%), and the Herpesviridae family (OR:1.41, 95% CI = 1.15–1.74; I2  = 12%) infection were associated with a higher risk of AD. No significant evidence of publication bias was found. Conclusion: These findings strengthened the evidence that infection may play an important role in AD. Additional research is required to determine whether treatment strategies targeting infectious diseases to prevent AD are viable in the future. Show more

Keywords: Alzheimer’s disease, Chlamydia pneumoniae, Herpesviridae, infectious, meta-analysis

DOI: 10.3233/JAD-191337

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Miyamoto, Masakazu | Kuzuya, Akira | Noda, Yasuha | Ueda, Sakiho | Asada-Utsugi, Megumi | Ito, Shinji | Fukusumi, Yoshiyasu | Kawachi, Hiroshi | Takahashi, Ryosuke | Kinoshita, Ayae

Article Type: Research Article

Abstract: Background: Given that amyloid-β (Aβ) peptide is produced and released at synapses, synaptic Aβ is one of the promising therapeutic targets to prevent synaptic dysfunction in Alzheimer’s disease (AD). Although Aβ production begins with the cleavage of the amyloid-β protein precursor (AβPP) by β-site AβPP cleaving enzyme 1 (BACE1), the mechanism on how BACE1 is involved in AβPP processing at synapses remains unclear. Objective: This study aimed to identify novel BACE1 interacting proteins regulating Aβ production at the synapse. Methods: BACE1 interacting proteins were pulled down using a mass spectrometry-based proteomics of wild-type (WT) rat brain …synaptoneurosome lysates utilizing anti-BACE1 antibody. Then, a novel BACE1 interactor was identified and characterized using experimental systems that utilized transfected cells and knockout (KO) mice. Results: Synaptic vesicle protein 2B (SV2B) was identified as a novel presynaptic interaction partner of BACE1. In HEK293 cells, co-overexpression of SV2B with BACE1 significantly reduced the sAβPPβ and Aβ levels released in the media; thus, SV2B overexpression negatively affected the AβPP cleavage by BACE1. Compared with those of WT mice, the hippocampal lysates of SV2B knockout mice had significantly elevated Aβ levels, whereas the β-secretase activity and the AβPP and BACE1 protein levels remained unchanged. Finally, a fractionation assay revealed that BACE1 was mislocalized in SV2B KO mice; hence, SV2B may be involved in BACE1 trafficking downregulating the amyloidogenic pathway of AβPP. Conclusion: SV2B has a novel role of negatively regulating the amyloidogenic processing of AβPP at the presynapses. Show more

Keywords: Alzheimer’s disease, amyloid-β , BACE1, SV2B, synapse

DOI: 10.3233/JAD-200071

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Garnier-Crussard, Antoine | Vernaudon, Julien | Auguste, Nicolas | Dauphinot, Virginie | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Neurocognitive disorders (NCD) are a growing health issue and the importance of diagnosis is still debated despite the benefits of making a diagnosis appearing to be greater than the risks. Objective: The aim of the present study was to explore the perception of the main benefits and risks to perform a diagnosis workup of NCD in a population of general practitioners (GPs), specialized physicians (SPs), other healthcare professionals (OHPs), and informal caregivers (ICs), and to identify the lowest perceived benefits and the highest perceived risks that could be levers to promote a diagnosis of NCD. …Methods: A standardized questionnaire was submitted to GPs, SPs, OHPs, and ICs aiming to evaluate the importance of eight benefits and eight risks related to NCD diagnosis (selected from the literature) for four prototypical clinical cases at different stages of the disease: subjective cognitive impairment/mild NCD, major NCD at mild/moderate stage, moderate stage with behavioral and psychotic symptoms, and severe stage. Results: The lowest perceived benefits of making an NCD diagnosis were “access to medical research”, “patient’s right to know”, and “initiation of symptomatic drug treatment”. The highest perceived risks of making an NCD diagnosis were “negative psychological impact for the patient”, “absence of disease-modifying treatment”, and “absence of suitable institution”. Conclusion: This study highlights the lowest perceived benefits and the highest perceived risks of making an NCD diagnosis. These benefits and risks could be modified to become levers to promote a personalized diagnosis of NCD. Show more

Keywords: Benefits and risks, ethical issues, neurocognitive disorders, personalized diagnosis, timely diagnosis

DOI: 10.3233/JAD-191253

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Jin, Jing | Guo, Jia | Cai, Hongbin | Zhao, Chongchong | Wang, Huan | Liu, Zhiyan | Ge, Zhao-Ming

Article Type: Research Article

Abstract: Many Alzheimer’s disease (AD) patients suffer from persistent neuropathic pain (NP), which is mediated, at least partially, but microglia. Nevertheless, the exact underlying mechanism is unknown. Moreover, a clinically translatable approach through modulating microglia for treating AD-associated NP is not available. Here, in a doxycycline-induced mouse model (rTg4510) for AD, we showed development of NP. We found that the total number of microglia in the CA3 region was not increased, but polarized to pro-inflammatory M1-like phenotype, with concomitant increases in production and secretion of pro-inflammatory cytokines. To examine whether this microglia polarization plays an essential role in the AD-associated NP, …we generated an adeno-associated virus (AAV) serotype PHP.B (capable of crossing the blood-brain barrier) carrying shRNA for DNA methyltransferase 1 (DNMT1) under a microglia-specific TMEM119 promoter (AAV-pTMEM119-shDNMT1), which specifically targeted microglia and induced a M2-like polarization in vitro and in vivo in doxycycline-treated rTg4510 mice. Intravenous infusion of AAV-pTMEM119-shDNMT1 induced M2-polarization of microglia and attenuated both AD-associated behavior impairment but also NP in the doxycycline-treated rTg4510 mice. Thus, our data suggest that AD-associated NP may be treated through M2-polarization of microglia. Show more

Keywords: Alzheimer’s disease, microglia polarization, neuropathic pain, shDNMT1

DOI: 10.3233/JAD-200099

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020