Journal of Alzheimer's Disease - Volume 77, issue 1

Authors: Kim, Jieun | Lee, Yujeong | Lee, Seulah | Kim, Kipom | Song, Minjung | Lee, Jaewon

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease worldwide, but its cause remains unclear. Although a few drugs can provide temporary and partial relief of symptoms in some patients, no curative treatment is available. Therefore, attention has been focused on research using stem cells to treat AD. Among stem cells, mesenchymal stem cells (MSCs) have been used to treat the related pathologies in animal models of AD, and other neurodegenerative disease. This review describes latest research trends on the use of MSC-based therapies in AD and its action of mechanism. MSCs have several beneficial effects. They would be …specified as the reduction of neuroinflammation, the elimination of amyloid-β, neurofibrillary tangles, and abnormal protein degradation, the promotion of autophagy-associated and blood-brain barrier recoveries, the upregulation of acetylcholine levels, improved cognition, and the recovery of mitochondrial transport. Therefore, this review describes the latest research trends in MSC-based therapy for AD by demonstrating the importance of MSC-based therapy and understanding of its mechanisms in AD and discusses the limitations and perspectives of stem cell therapy in AD. Show more

Keywords: Alzheimer’s disease, mesenchymal stem cells, stem cell therapy

DOI: 10.3233/JAD-200219

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 1-14, 2020

Authors: Zhang, Li-Na | Li, Meng-Jie | Shang, Ying-Hui | Zhao, Fan-Fan | Huang, Han-Chang | Lao, Feng-Xue

Article Type: Review Article

Abstract: The ɛ 4 allele of the Apolipoprotein E (APOE ) gene in individuals infected by Herpes simplex virus type 1 (HSV-1) has been demonstrated to be a risk factor in Alzheimer’s disease (AD). APOE -ɛ 4 reduces the levels of neuronal cholesterol, interferes with the transportation of cholesterol, impairs repair of synapses, decreases the clearance of neurotoxic peptide amyloid-β (Aβ), and promotes the deposition of amyloid plaque, and eventually may cause development of AD. HSV-1 enters host cells and can infect the olfactory system, trigeminal ganglia, entorhinal cortex, and hippocampus, and may cause AD-like pathological changes. The lifecycle of HSV-1 …goes through a long latent phase. HSV-1 induces neurotropic cytokine expression with pro-inflammatory action and inhibits antiviral cytokine production in AD. It should be noted that interferons display antiviral activity in HSV-1-infected AD patients. Reactivated HSV-1 is associated with infectious burden in cognitive decline and AD. Finally, HSV-1 DNA has been confirmed as present in human brains and is associated with APOE ɛ 4 in AD. HSV-1 and APOE ɛ 4 increase the risk of AD and relate to abnormal autophagy, higher concentrations of HSV-1 DNA in AD, and formation of Aβ plaques and neurofibrillary tangles. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, cytokine, estrogen therapy, herpes simplex virus type 1, infectious burden, interferon

DOI: 10.3233/JAD-200607

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 15-31, 2020

Authors: Calfio, Camila | Gonzalez, Andrea | Singh, Sandeep Kumar | Rojo, Leonel E. | Maccioni, Ricardo B.

Article Type: Review Article

Abstract: One of the major challenges of medical sciences has been finding a reliable compound for the pharmacological treatment of Alzheimer’s disease (AD). As most of the drugs directed to a variety of targets have failed in finding a medical solution, natural products from Ayurvedic medicine or nutraceutical compounds emerge as a viable preventive therapeutics’ pathway. Considering that AD is a multifactorial disease, nutraceutical compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs used for AD treatment. We review in-depth important medicinal plants …that have been already investigated for therapeutic uses against AD, focusing on a diversity of pharmacological actions. These targets include inhibition of acetylcholinesterase, β-amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc., and pharmacological actions so diverse as anti-inflammatory, memory enhancement, nootropic effects, glutamate excitotoxicity, anti-depressants, and antioxidants. In addition, we also discuss the activity of nutraceutical compounds and phytopharmaceuticals formulae, mainly directed to tau protein aggregates mechanisms of action. These include compounds such as curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and meganatural-az and other phytochemicals such as huperzine A, limonoids, azaphilones, and aged garlic extract. Finally, we revise the nutraceutical formulae BrainUp-10 composed of Andean shilajit and B-complex vitamins, with memory enhancement activity and the control of neuropsychiatric distress in AD patients. This integrated view on nutraceutical opens a new pathway for future investigations and clinical trials that are likely to render some results based on medical evidence. Show more

Keywords: Alzheimer’s disease, anti-tau molecules, disease prevention and treatment, mechanisms, multitarget approaches, nutraceutical compounds

DOI: 10.3233/JAD-200443

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 33-51, 2020

Authors: Schaefer, Sydney Y. | Hooyman, Andrew | Duff, Kevin

Article Type: Short Communication

Abstract: Affordable, noninvasive methods of predicting functional decline are needed for individuals at risk for Alzheimer’s disease. This study tested whether a timed upper-extremity motor task predicted functional decline over one year in 79 adults diagnosed with amnestic mild cognitive impairment. Participants completed subjective and objective measures of daily functioning at baseline and one year later. Motor task performance and delayed memory were also evaluated at baseline. Motor task performance was a significant predictor of one-year follow-up daily functioning, improving model fits by 18– 35%. Thus, motor behavior has potential to be an affordable enrichment strategy that is sensitive to functional …decline. Show more

Keywords: Activities of daily living, functional decline, mild cognitive impairment, motor behavior

DOI: 10.3233/JAD-200518

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 53-58, 2020

Authors: Singh, Pradeep K. | Chen, Zu-Lin | Strickland, Sidney | Norris, Erin H.

Article Type: Short Communication

Abstract: An activated plasma contact system is an abnormality observed in many Alzheimer’s disease (AD) patients. Since mild cognitive impairment (MCI) patients often develop AD, we analyzed the status of contact system activation in MCI patients. We found that kallikrein activity, high molecular weight kininogen cleavage, and bradykinin levels— measures of contact system activation— were significantly elevated in MCI patient plasma compared to plasma from age- and education-matched healthy individuals. Changes were more pronounced in MCI patients with impaired short-term recall memory, indicating the possible role of the contact system in early cognitive changes.

Keywords: Alzheimer’s disease, bradykinin, contact activation, high molecular weight kininogen, memory impairment, mild cognitive impairment, plasma kallikrein

DOI: 10.3233/JAD-200343

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 59-65, 2020

Authors: Li, Jingwen | Long, Xi | Huang, Heqing | Tang, Jine | Zhu, Chunli | Hu, Shaoping | Wu, Jing | Li, Jinghong | Lin, Zhicheng | Xiong, Nian

Article Type: Research Article

Abstract: Background: Facing the novel coronavirus disease 2019 (COVID-19), most vulnerable individuals are seniors, especially those with comorbidities. More attention needs to been paid to the COVID-19 patients with Alzheimer’s disease (AD), which is the top age-related neurodegenerative disease. Objective: Since it is unclear whether AD patients are prone to COVID-19 infection and progression to severe stages, we report for the first time a retrospective analysis of the clinical characteristics of AD patients with COVID-19 pneumonia. Methods: We conducted a retrospective cohort study of the clinical data of 19 AD patients with COVID-19 pneumonia, compared with 23 …non-AD COVID-19 patients admitted at the same time to our hospital. Demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Results: Between AD patients and non-AD patients with COVID-19 pneumonia, the pneumonia severity was not significantly different. AD patients had a higher clustering onset than non-AD patients. The median duration from symptom onset to hospitalization were shorter in AD patients than non-AD patients, indicating the former were sent to the hospital by their family or from nursing home earlier than the later. The median duration from hospitalization to discharge seemed shorter in AD patients than non-AD patients. Dementia patients seemed less likely to report fatigue. It is noticed that more AD patients might have pericardial effusion than the non-AD patients. Conclusion: AD patients with COVID-19 were in milder conditions with a better prognosis than non-AD patients. AD patients who had adequate access to healthcare showed resilience to COVID-19 with shorter hospital stays. Show more

Keywords: Alzheimer’s disease, clinical characteristics, COVID-19

DOI: 10.3233/JAD-200649

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 67-73, 2020

Authors: Cai, Hong-Bin | Fan, Zhen-Zhen | Tian, Ting | Li, Zi-Chao | Zhao, Chong-Chong | Guo, Wen-Ting | Ge, Zhao-Ming

Article Type: Research Article

Abstract: The connection between diabetes and Alzheimer’s disease (AD) is not fully determined. Hyperphosphorylation of tau protein is mediated by binding and stabilization of truncated p25 with cyclin-dependent kinase-5 (CDK5) in AD. We recently showed that diabetes-associated hyperglycemia increased the CDK5 levels to promote development of AD. Here, we examined the underlying mechanisms. Hyperglycemia and glucose intolerance were induced in rats that had received a low dose of streptozotocin (STZ) and a high fat diet (HFD). Compared to the control rats that received no STZ and normal diet-fed, the STZ + HFD rats exhibited poorer performance in the behavioral test and showed hyperacetylation …of H3K9 histone on CDK5 promoter, likely resulting from upregulation of a histone acetyltransferase, GCN5. Inhibition of acetylation of H3K9 histone by a specific GCN5 inhibitor, MB3, attenuated activation of CDK5, resulting in decreased tau phosphorylation in rat brain and improved performance of the rats in the behavior test. Thus, these data suggest that diabetes may promote future development of AD through hyperacetylation of H3K9 histone on CDK5 promoter. Show more

Keywords: Alzheimer’s disease, cyclin-dependent kinase-5, diabetes, GCN5, H3K9 hyperacetylation, tau

DOI: 10.3233/JAD-200163

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 75-84, 2020

Authors: Gao, Yiwen | Zhang, Nan | Lv, Chunmei | Li, Na | Li, Xueqin | Li, Weiwei

Article Type: Research Article

Abstract: Background: Long noncoding RNAs have been proven to play an important role in the progression of Alzheimer’s disease (AD). However, the function of small nucleolar RNA host gene 1 (SNHG1) in AD progression remains to be studied. Objective: To explore the role of SNHG1 in AD progression and clarify its potential mechanism. Methods: Amyloid β-protein (Aβ) was used to construct an AD cell model in vitro . The expression levels of SNHG1 and miR-361-3p were determined by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit 8 assay and flow …cytometry. The levels of apoptosis-related proteins and zinc finger gene 217 (ZNF217) protein were evaluated by western blot analysis. Additionally, the contents of inflammatory cytokines and oxidative stress markers were tested by enzyme-linked immunosorbent assay. Furthermore, dual-luciferase reporter and RNA immunoprecipitation assays were used to verify the interaction between miR-361-3p and SNHG1 or ZNF217. Results: Aβ could induce cell injury, while resveratrol could reverse this effect. SNHG1 expression was positively regulated by Aβ and negatively regulated by resveratrol. SNHG1 knockdown could reverse the promotion effect of Aβ on cell injury. Moreover, SNHG1 sponged miR-361-3p, and miR-361-3p targeted ZNF217. Additionally, miR-361-3p overexpression reversed the promotion effect of SNHG1 overexpression on cell injury, and ZNF217 silencing also reversed the promotion effect of miR-361-3p inhibitor on cell injury. Conclusion: SNHG1 promoted cell injury by regulating the miR-361-3p/ZNF217 axis, which might provide a theoretical basis for molecular therapy of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , miR-361-3p, resveratrol, SNHG1, ZNF217

DOI: 10.3233/JAD-191303

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 85-98, 2020

Authors: Rejc, Luka | Gómez-Vallejo, Vanessa | Rios, Xabier | Cossío, Unai | Baz, Zuriñe | Mujica, Edurne | Gião, Tiago | Cotrina, Ellen Y. | Jiménez-Barbero, Jesús | Quintana, Jordi | Arsequell, Gemma | Cardoso, Isabel | Llop, Jordi

Article Type: Research Article

Abstract: Background: Transthyretin (TTR) is a tetrameric, amyloid-β (Aβ)-binding protein, which reduces Aβ toxicity. The TTR/Aβ interaction can be enhanced by a series of small molecules that stabilize its tetrameric form. Hence, TTR stabilizers might act as disease-modifying drugs in Alzheimer’s disease. Objective: We monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF), which acts as small-molecule chaperone of the TTR/Aβ interaction, and tolcapone, which does not behave as a small-molecule chaperone, in an animal model of Alzheimer’s disease using positron emission tomography (PET). Methods: Female mice (AβPPswe/PS1A246E/TTR+/–) were divided into 3 groups (n  = 7 per …group): IDIF-treated, tolcapone-treated, and non-treated. The oral treatment (100 mg/Kg/day) was started at 5 months of age. Treatment efficacy assessment was based on changes in longitudinal deposition of Aβ in the hippocampus (HIP) and the cortex (CTX) and determined using PET-[18 F]florbetaben. Immunohistochemical analysis was performed at age = 14 months. Results: Standard uptake values relative to the cerebellum (SUVr) of [18 F]florbetaben in CTX and HIP of non-treated animals progressively increased from age = 5 to 11 months and stabilized afterwards. In contrast, [18 F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages = 5 and 11 months and significantly increased at 14 months. In the tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in the non-treated group. No significant treatment effect was observed in CTX. Results from immunohistochemistry matched the in vivo data at age = 14 months. Conclusion: Our work provides encouraging preliminary results on the ability of small-molecule chaperones to ameliorate Aβ deposition in certain brain regions. Show more

Keywords: Alzheimer’s disease, disease-modifying drug, positron emission tomography, small-molecule chaperones, transthyretin, TTR/Aβ interaction

DOI: 10.3233/JAD-200570

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 99-112, 2020

Authors: Roccaro, Ilaria | Smirni, Daniela

Article Type: Research Article

Abstract: Background: A system of photosensitive retinal ganglion cells provides ‘non-visual’ information on the circadian sequences of light to the suprachiasmatic nucleus (SCN), which, as the ‘master clock’, synchronizes the chronobiological mechanisms of all the biological clocks. Damage to SCN structure alters circadian behavioral and hormonal rhythms and interferes with a regular sleep-wake pattern. Several studies have shown that, in aging and in Alzheimer’s disease (AD), circadian rhythms change their synchronization with the environment and behavior loses sync with light. Objective: The current overview aims to examine research studies showing the effect of bright light therapy (BLT) on sleep …disorders and sleep-wake patterns in AD. Methods: A literature search was conducted, taking into consideration the relevant studies over the last 20 years. Fifteen studies have been thorough: seven followed an environmental-architectural approach and eight followed a treatment devices approach. Results: Studies agree in considering BLT as a promising non-pharmacological intervention to compensate for circadian rhythm alterations and they support the need for standardized protocols that allow a comparison between multicenter studies. Conclusion: Interestingly, in an attempt to contain the spread of the COVID-19 pandemic, health authorities have forced the population to stay home. Therefore, AD people are not currently able to enjoy exposure to sunlight. It is predictable that they may experience an exacerbation of circadian disturbances and that the BLT can be an effective response to prevent such exacerbation. Show more

Keywords: Alzheimer’s disease, biological clocks, bright light therapy, circadian rhythms, light boxes, retinal ganglion cells, sleep disorder, suprachiasmatic nucleus

DOI: 10.3233/JAD-200478

Citation: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 113-125, 2020