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

Authors: Dorey, C. Kathleen | Gierhart, Dennis | Fitch, Karlotta A. | Crandell, Ian | Craft, Neal E.

Article Type: Review Article

Abstract: Background: Oxidative stress contributes to pathogenesis and progression of Alzheimer’s disease (AD). Higher levels of the dietary antioxidants— carotenoids and tocopherols— are associated with better cognitive functions and lower risk for AD, and lower levels of multiple carotenoids are found in serum and plasma of patients with AD. Although brains donated by individuals with mild cognitive impairment had significantly lower levels of lutein and beta-carotene, previous investigators found no significant difference in carotenoid levels of brains with AD and cognitively normal brains. Objective: This study tested the hypothesis that micronutrients are significantly lower in donor brains with AD …than in healthy elderly brains. Methods: Samples of donor brains with confirmed AD or verified health were dissected into grey and white matter, extracted with organic solvents and analyzed by HPLC. Results: AD brains had significantly lower levels of lutein, zeaxanthin, anhydrolutein, retinol, lycopene, and alpha-tocopherol, and significantly increased levels of XMiAD, an unidentified xanthophyll metabolite. No meso-zeaxanthin was detected. The overlapping protective roles of xanthophylls, carotenes, α- and γ -tocopherol are discussed. Conclusion: Brains with AD had substantially lower concentrations of some, but not all, xanthophylls, carotenes, and tocopherols, and several-fold higher concentrations of an unidentified xanthophyll metabolite increased in AD (XMiAD). Show more

Keywords: Alzheimer’s disease, antioxidants, brain, carotenoids, deficiency, lutein, lycopene, meso-zeaxanthin, oxidation, tocopherols, zeaxanthin

DOI: 10.3233/JAD-220460

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Zhang, Ruxin | Song, Yanrong | Su, Xuefeng

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is considered to be the most common neurodegenerative disease, with clinical symptoms encompassing progressive memory loss and cognitive impairment. Necroptosis is a form of programmed necrosis that promotes cell death and neuroinflammation, which further mediates the pathogenesis of several neurodegenerative diseases, especially AD. Current evidence has strongly suggested that necroptosis is activated in AD brains, resulting in neuronal death and cognitive impairment. We searched the PubMed database, screening all articles published before September 28, 2022 related to necroptosis in the context of AD pathology. The keywords in the search included: “necroptosis”, “Alzheimer’s disease”, “signaling pathways”, “Aβ”, Aβo”, …“Tau”, “p-Tau”, “neuronal death”, “BBB damage”, “neuroinflammation”, “microglia”, “mitochondrial dysfunction”, “granulovacuolar degeneration”, “synaptic loss”, “axonal degeneration”, “Nec-1”, “Nec-1s”, “GSK872”, “NSA”, “OGA”, “RIPK1”, “RIPK3”, and “MLKL”. Results show that necroptosis has been involved in multiple pathological processes of AD, including amyloid-β aggregation, tau accumulation, neuronal death, and blood-brain barrier damage, etc. More importantly, existing research on AD necroptosis interventions, including drug intervention and potential gene targets, as well as its current clinical development status, was discussed. Finally, the issues pertaining to necroptosis in AD were presented. Accordingly, this review may provide further insight into clinical perspectives and challenges for the future treatment of AD by targeting the necroptosis pathway. Show more

Keywords: Alzheimer’s disease, granulovacuolar degeneration, mitochondrial dysfunction, MLKL, necroptosis, neurodegeneration, neuronal death, RIPK1, RIPK3

DOI: 10.3233/JAD-220809

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2022

Authors: Surya, Kumar | Manickam, Nivethitha | Jayachandran, Kesavan Swaminathan | Kandasamy, Mahesh | Anusuyadevi, Muthuswamy

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling …have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD. Show more

Keywords: Adult neurogenesis, Alzheimer’s disease, cell cycle, hippocampus, resveratrol, Sirtuin1, Wnt pathway

DOI: 10.3233/JAD-220559

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2022

Authors: Shirgadwar, Shubhendu M. | Kumar, Rahul | Preeti, Kumari | Khatri, Dharmendra Kumar | Singh, Shashi Bala

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is an age-related progressive multifactorial, neurodegenerative disease. The autophagy and Keap1-Nrf2 axis system are both implicated in the oxidative-stress response, metabolic stress, and innate immunity, and their dysregulation is associated with pathogenic processes in PD. Phloretin (PLT) is a phenolic compound reported possessing anti-inflammatory and antioxidant activities. Objective: To evaluate the neuroprotective potential of PLT in PD via modulating the autophagy-antioxidant axis Methods: The neuroprotective effect of PLT was evaluated in vitro using rotenone (ROT) exposed SH-SY5Y cell line and in vivo using ROT administered C57BL/6 mice. Mice were administered …with PLT (50 and 100 mg/kg, p.o.) concomitantly with ROT (1 mg/kg, i.p) for 3 weeks. Locomotive activity and anxiety behaviors were assessed using rotarod and open field tests respectively. Further apoptosis (Cytochrome-C, Bax), α -Synuclein (α -SYN), tyrosine hydroxylase (TH), antioxidant proteins (nuclear factor erythroid 2-related factor 2 (NRF2), and heme oxygenase-1 (HO-1), autophagic (mTOR, Atg5,7, p62, Beclin, and LC3B-I/II), were evaluated both in in vitro and in vivo . Results: PLT improved locomotive activity and anxiety-like behavior in mice. Further PLT diminished apoptotic cell death, and α -SYN expression and improved the expression of TH, antioxidant, and autophagic regulating protein. Conclusion: Taken together, present data deciphers that the PLT effectively improves motor and non-motor symptoms via modulating the mTOR/NRF2/p62 pathway-mediated feedback loop. Hence, PLT could emerge as a prospective disease-modifying drug for PD management. Show more

Keywords: Apoptosis, autophagy, oxidative stress, Parkinson’s disease, phloretin

DOI: 10.3233/JAD-220793

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Zhou, Yujia | Dong, Jingyi | Song, Jingmei | Lvy, Chaojie | Zhang, Yuyan

Article Type: Research Article

Abstract: Background: Considering the strong correlation made between Alzheimer’s disease (AD) and the pathology of glucose metabolism disorder, we sought to analyze the effects of fasting blood glucose (FBG) level, fasting plasma insulin (FINS) level, and insulin resistance index (HOMA-IR) on the risk and severity of AD. Objective: Reveal the pathological relationship between AD and insulin resistance. Methods: We searched 5 databases from inception through April 4, 2022. Meta-regression was conducted to identify if there were significant differences between groups. Shapiro-Wilk test and the Q-Q diagram were applied to evaluate the normality of variables. A multiple logistic …regression model was employed to explore the association between FBG, FINS, HOMA-IR, and Mini-Mental State Examination scale score (MMSE). Results: 47 qualified articles including 2,981 patients were enrolled in our study. FBG (p  < 0.001), FINS (p  < 0.001), and HOMA-IR (p  < 0.001) were higher in AD patients than in controls. HOMA-IR was negatively correlated with MMSE (p  = 0.001) and positively related to the sex ratio (male versus female) (p  < 0.05). HOMA-IR obeyed lognormal distribution (p  > 0.05), and the 95% bilateral boundary values were 0.73 and 10.67. FBG (p  = 0.479) was positively correlated to MMSE, while FINS (p  = 0.1657) was negatively correlated with MMSE. Conclusion: The increase in the levels of FBG, FINS, and HOMA-IR served as precise indicators of the risk of AD. HOMA-IR was found to be correlated to the increasing severity of AD, especially in male AD patients. Show more

Keywords: Alzheimer’s disease, disease degree, glucose metabolism, incidence risk, systematic analysis

DOI: 10.3233/JAD-220751

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Castillo, Carolina | Bravo-Arrepol, Gastón | Wendt, Aline | Saez-Orellana, Francisco | Millar, Camila | Burgos, Carlos F. | Gavilán, Javiera | Pacheco, Carla | Ahumada-Rudolph, Ramón | Napiórkowska, Mariola | Pérez, Claudia | Becerra, José | Fuentealba, Jorge | Cabrera-Pardo, Jaime R.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana …, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects. Objective: In this study, the neuroprotective abilities of Eu on synaptic failure induced by AβOs were analyzed. Methods: Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AβOs. Results: In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AβOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AβOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aβ aggregation process inducing a decrease in AβOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu. Conclusion: We believe that Eu represents a novel lead that reduces the Aβ toxicity, opening new research venues for lignans as neuroprotective agents. Show more

Keywords: Aβ interaction, Alzheimer’s disease, amyloid-β peptide, eudesmin, neuroprotection

DOI: 10.3233/JAD-220935

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Yeap, Yee Jie | Kandiah, Nagaendran | Nizetic, Dean | Lim, Kah-Leong

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia that affects millions of predominantly elderly individuals worldwide. Despite intensive research over several decades, controversies still surround the etiology of AD and the disease remains incurable. Meanwhile, new molecular players of the central amyloid cascade hypothesis have emerged and among these is a protease known as β-site APP cleavage enzyme 2 (BACE2). Unlike BACE1, BACE2 cleaves the amyloid-β protein precursor within the Aβ domain that accordingly prevents the generation of Aβ42 peptides, the aggregation of which is commonly regarded as the toxic entity that drives neurodegeneration in AD. Given …this non-amyloidogenic role of BACE2, it is attractive to position BACE2 as a therapeutic target for AD. Indeed, several groups including ours have demonstrated a neuroprotective role for BACE2 in AD. In this review, we discuss emerging evidence supporting the ability of BACE2 in mitigating AD-associated pathology in various experimental systems including human pluripotent stem cell-derived cerebral organoid disease models. Alongside this, we also provide an update on the identification of single nucleotide polymorphisms occurring in the BACE2 gene that are linked to increased risk and earlier disease onset in the general population. In particular, we highlight a recently identified point mutation on BACE2 that apparently leads to sporadic early-onset AD. We believe that a better understanding of the role of BACE2 in AD would provide new insights for the development of viable therapeutic strategies for individuals with dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor secretase, beta-secretase, neuroprotection

DOI: 10.3233/JAD-220867

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Chen, Xiaokun | Jiang, Shenzhong | Wang, Renzhi | Bao, Xinjie

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), a progressive dementia, is one of the world’s most dangerous and debilitating diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Further understanding of the mechanisms underlying AD and the development of novel therapeutic options are critical. Neurogenesis is impaired in AD, which contributes to memory deficits. Transplanted neural stem cells (NSCs) can regenerate degraded cholinergic neurons, and new neurons derived from NSCs can form synaptic connections with neighboring neurons. In theory, …employing NSCs to replace and restore damaged cholinergic neurons and brain connections may offer new treatment options for AD. However there remain barriers to surmount before NSC-based therapy can be used clinically. The objective of this article is to describe recent advances in the treatment of AD models and clinical trials involving NSCs. In addition, we discuss the challenges and prospects associated with cell transplant therapy for AD. Show more

Keywords: Alzheimer’s disease, cell therapy, neural stem cells, neurodegenerative disease, transplantation

DOI: 10.3233/JAD-220721

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Huang, Li | Lu, Zhaogang | Zhang, Hexin | Wen, Hongyong | Li, Zongji | Liu, Qibing | Wang, Rui

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide. The accumulation of amyloid-β (Aβ) protein and plaque formation in the brain are two major causes of AD. Interestingly, growing evidence demonstrates that the gut flora can alleviate AD by affecting amyloid production and metabolism. However, the underlying mechanism remains largely unknown. This review will discuss the possible association between the gut flora and Aβ in an attempt to provide novel therapeutic directions for AD treatment based on the regulatory effect of Aβ on the gut flora.

Keywords: Alzheimer’s disease, amyloid-β, colitis, insulin resistance, intestinal flora, neuroinflammation

DOI: 10.3233/JAD-220651

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Krishna, Geethu | Santhoshkumar, Rashmi | Sivakumar, Palanimuthu Thangaraju | Alladi, Suvarna | Mahadevan, Anita | Dahale, Ajit B. | Arshad, Faheem | Subramanian, Sarada

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are pathologically distinct neurodegenerative disorders with certain overlap in cognitive and behavioral symptoms. Both AD and FTD are characterized by synaptic loss and accumulation of misfolded proteins, albeit, in different regions of the brain. Objective: To investigate the synaptic and organellar markers in AD and FTD through assessment of the levels of synaptic protein, neurogranin (Ng) and organellar proteins, mitofusin-2 (MFN-2), lysosomal associated membrane protein-2 (LAMP-2), and golgin A4 from neuronal exosomes. Methods: Exosomes isolated from the plasma of healthy controls (HC), AD and FTD subjects were characterized …using transmission electron microscopy. Neurodegenerative status was assessed by measurement of neurofilament light chain (NfL) using Simoa. The pooled exosomal extracts from each group were analyzed for Ng, MFN-2, LAMP-2, and golgin A4 by western blot analysis using enhanced chemiluminescence method of detection. Results: The densitometric analysis of immunoreactive bands demonstrated a 65% reduction of Ng in AD and 53% in FTD. Mitochondrial protein MFN-2 showed a significant reduction by 32% in AD and 46% in FTD. Lysosomal LAMP-2 and Golgi complex associated golgin A4 were considerably increased in both AD and FTD. Conclusion: Changes in Ng may reflect the ongoing synaptic degeneration that are linked to cognitive disturbances in AD and FTD. Importantly, the rate of synaptic degeneration was more pronounced in AD. Changes to a similar extent in both the dementia groups in organellar proteins indicates shared mechanisms of protein accumulation/degradation common to both AD and FTD. Show more

Keywords: Alzheimer’s disease, exosomes, frontotemporal dementia, golgin A4, immunoblotting, LAMP-2, MFN-2, neurogranin

DOI: 10.3233/JAD-220829

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022