scholarly journals Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer’s Disease and Ischemia-Related Brain Injury

2020 ◽  
Vol 13 (11) ◽  
pp. 379
Author(s):  
Michał Wiciński ◽  
Eryk Wódkiewicz ◽  
Karol Górski ◽  
Maciej Walczak ◽  
Bartosz Malinowski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Damage ◽  
Neurovascular Unit ◽  
Neuronal Loss ◽  
Impact Risk ◽  
Sglt2 Inhibition ◽  
The Central Nervous System ◽  
Cortical Regions ◽  
Endothelial Growth Factor

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are oral anti-hyperglycemic agents approved for the treatment of type 2 diabetes mellitus. Some reports suggest their presence in the central nervous system and possible neuroprotective properties. SGLT2 inhibition by empagliflozin has shown to reduce amyloid burden in cortical regions of APP/PS1xd/db mice. The same effect was noticed regarding tau pathology and brain atrophy volume. Empagliflozin presented beneficial effect on cognitive function, which may be connected to an increase in cerebral brain-derived neurotrophic factor. Canagliflozin and dapagliflozin may possess acetylcholinesterase inhibiting activity, resembling in this matter Alzheimer’s disease-registered therapies. SGLT2 inhibitors may prove to impact risk factors of atherosclerosis and pathways participating both in acute and late stage of stroke. Their mechanism of action can be related to induction in hepatocyte nuclear factor-1α, vascular endothelial growth factor-A, and proinflammatory factors limitation. Empagliflozin may have a positive effect on preservation of neurovascular unit in diabetic mice, preventing its aberrant remodeling. Canagliflozin seems to present some cytostatic properties by limiting both human and mice endothelial cells proliferation. The paper presents potential mechanisms of SGLT-2 inhibitors in conditions connected with neuronal damage, with special emphasis on Alzheimer’s disease and cerebral ischemia.

scholarly journals Human brain organoids in Alzheimer’s disease

Organoid ◽  
2021 ◽  
Vol 1 ◽  
pp. e5
Author(s):  
You Jung Kang ◽  
Hansang Cho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Damage ◽  
Three Dimensional ◽  
Neuronal Loss ◽  
Model Systems ◽  
Key Characteristics ◽  
Brain Organoid ◽  
Human Brains ◽  
The Brain

Alzheimer’s disease (AD) is a progressive neurological disorder that typically involves neuronal damage leading to the deterioration of cognitive and essential body functions in aging brains. Major signatures of AD pathology include the deposition of amyloid plaques and neurofibrillary tangles, disruption of the blood-brain barrier, and induction of hyper-activated proinflammation in the brain, leading to synaptic impairment and neuronal loss. However, conventional pharmacotherapeutic modalities merely alleviate symptoms, but do not cure AD, partly because drug screening has used model systems with limited accuracy in terms of reflecting AD pathology in human brains. In this regard, several AD organoids have received substantial attention as alternatives to AD animal models. In this review, we summarize the key characteristics required for the generation of a pathologically relevant AD brain organoid. We also overview major experimental organoid models of AD brains, such as spheroids, three-dimensional (3D) bioprinted constructs, and 3D brain-on-chips, and discuss their strengths and weaknesses for AD research. This review will provide valuable information that will inspire future efforts to engineer authentic AD organoids for the study of AD pathology and for the discovery of novel AD therapeutic strategies.

scholarly journals Microglia, TREM2, and Therapeutic Methods of Alzheimer’s Disease

2021 ◽  
Author(s):  
Siwei Xu ◽  
Yaya Ji ◽  
Tianle Sha ◽  
Haoming Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dynamic Change ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Pathological Process ◽  
Amyloid Β Protein ◽  
Transmembrane Glycoprotein ◽  
Β Protein ◽  
The Central Nervous System

Alzheimer’s disease (AD) is one of the most common causes of dementia all around the world. It is characterized by the deposition of amyloid-β protein (Aβ) and the formation of neurofibrillary tangles (NFTs), which contribute to neuronal loss and cognitive decline. Microglia, as innate immune cells in brain, plays dual roles in the pathological process of AD. Expression in different subtypes of microglia is diverse in AD genes. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane glycoprotein mainly expressed on microglia in the central nervous system (CNS). Soluble TREM2 (sTREM2), a proteolytic product of TREM2, which is abundant in the cerebrospinal fluid, shows a dynamic change in different stages and ameliorates the pathological process of AD. The interplay between the different subtypes of apolipoprotein and TREM2 is closely related to the mechanism of AD and serves as important regulatory sites. Moreover, several therapeutic strategies targeting TREM2 have shown positive outcomes during clinical trials and some novel therapies at different points are in progress. In this review, we mainly talk about the interrelationships among microglia, TREM2, and AD, and hope to give an overview of the strategies of AD.

scholarly journals Biomarkers for Alzheimer’s Disease Early Diagnosis

2020 ◽  
Vol 10 (3) ◽  
pp. 114 ◽  
Author(s):  
Eva Ausó ◽  
Violeta Gómez-Vicente ◽  
Gema Esquiva
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Loss ◽  
Diagnostic Tools ◽  
Csf Biomarkers ◽  
Diagnosis And Prognosis ◽  
Positron Emission ◽  
The Central Nervous System ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

Alzheimer’s disease (AD) is the most common cause of dementia, affecting the central nervous system (CNS) through the accumulation of intraneuronal neurofibrillary tau tangles (NFTs) and β-amyloid plaques. By the time AD is clinically diagnosed, neuronal loss has already occurred in many brain and retinal regions. Therefore, the availability of early and reliable diagnosis markers of the disease would allow its detection and taking preventive measures to avoid neuronal loss. Current diagnostic tools in the brain, such as magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, and cerebrospinal fluid (CSF) biomarkers (Aβ and tau) detection are invasive and expensive. Brain-secreted extracellular vesicles (BEVs) isolated from peripheral blood have emerged as novel strategies in the study of AD, with enormous potential as a diagnostic evaluation of therapeutics and treatment tools. In addition; similar mechanisms of neurodegeneration have been demonstrated in the brain and the eyes of AD patients. Since the eyes are more accessible than the brain, several eye tests that detect cellular and vascular changes in the retina have also been proposed as potential screening biomarkers. The aim of this study is to summarize and discuss several potential markers in the brain, eye, blood, and other accessible biofluids like saliva and urine, and correlate them with earlier diagnosis and prognosis to identify individuals with mild symptoms prior to dementia.

scholarly journals TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Anusha Jayaraman ◽  
Thein Than Htike ◽  
Rachel James ◽  
Carmen Picon ◽  
Richard Reynolds
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pyramidal Neurons ◽  
Neuronal Damage ◽  
Neuronal Loss ◽  
Post Mortem ◽  
Altered Expression ◽  
Neuron Density ◽  
Show Evidence ◽  
Human Ipsc

AbstractThe pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3 + and phosphoMLKL + neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons, in response to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway.

scholarly journals Ficus erecta Thunb. Leaves Ameliorate Cognitive Deficit and Neuronal Damage in a Mouse Model of Amyloid-β-Induced Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Eunjin Sohn ◽  
Yu Jin Kim ◽  
Joo-Hwan Kim ◽  
Soo-Jin Jeong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Inflammatory Cytokines ◽  
Cognitive Deficit ◽  
Neuronal Damage ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Bdnf Signaling ◽  
Brain Tissues

Alzheimer’s disease (AD) pathogenesis is linked to amyloid plaque accumulation, neuronal loss, and brain inflammation. Ficus erecta Thunb. is a food and medicinal plant used to treat inflammatory diseases. Here, we investigated the neuroprotective effects of F. erecta Thunb. against cognitive deficit and neuronal damage in a mouse model of amyloid-β (Aβ)-induced AD. First, we confirmed the inhibitory effects of ethanol extracts of F. erecta (EEFE) leaves on Aβ aggregation in vivo and in vitro. Next, behavioral tests (passive avoidance task and Morris water maze test) revealed EEFE markedly improved cognitive impairment in Aβ-injected mice. Furthermore, EEFE reduced neuronal loss and the expression of neuronal nuclei (NeuN), a neuronal marker, in brain tissues of Aβ-injected mice. EEFE significantly reversed Aβ-induced suppression of cAMP response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression, indicating neuroprotection was mediated by the CREB/BDNF signaling. Moreover, EEFE significantly suppressed the inflammatory cytokines interleukin 1beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and expression of ionized calcium-binding adaptor molecule 1 (Iba-1), a marker of microglial activation, in brain tissues of Aβ-injected mice, suggesting anti-neuroinflammatory effects. Taken together, EEFE protects against cognitive deficit and neuronal damage in AD-like mice via activation of the CREB/BDNF signaling and upregulation of the inflammatory cytokines.

Retinal Changes in Transgenic Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Li Guo ◽  
Nivedita Ravindran ◽  
Daniel Hill ◽  
M. Francesca Cordeiro
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Immunohistochemical Analysis ◽  
Therapeutic Effects ◽  
The Central Nervous System ◽  
New Treatments ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder, the most common form of dementia. AD is characterized by amyloid-ß (Aß) plaques and neurofibrillary tangles (NFT) in the brain, in association with neuronal loss and synaptic failure, causing cognitive deficits. Accurate and early diagnosis is currently unavailable in lifespan, hampering early intervention of potential new treatments. Visual deficits have been well-documented in AD patients, and the pathological changes identified in the brain are also believed to be found in the retina, an integral part of the central nervous system. Retinal changes can be detected by real-time non-invasive imaging due to the transparent nature of the ocular media, potentially allowing an earlier diagnosis as well as monitoring disease progression and treatment outcome. Animal models are essential for AD research, and this review has a focus on retinal changes in various transgenic AD mouse models with retinal imaging and immunohistochemical analysis as well as therapeutic effects in those models. We also discuss the limitations of transgenic AD models in clinical translations.

Association of Polymorphisms of the Tissue Inhibitors of Metalloproteinases-1 and -2 with Alzheimer’s Disease in Taiwan

2021 ◽  
Vol 18 ◽  
Author(s):  
Wei-Min Ho ◽  
Yun-Shien Lee ◽  
Chiung-Mei Chen ◽  
Yah-Yuan Wu ◽  
Wen-Chuin Hsu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Neuronal Loss ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Protective Effects ◽  
Tissue Inhibitors ◽  
Toxic Reaction ◽  
Empirical Estimates ◽  
Minor Alleles

Background: Alzheimer’s disease (AD) leads to progressive neuronal loss and cognitive and behavioral decline in the aging population. Matrix metalloproteinases (MMPs) and associated tissue inhibitors of metalloproteinases (TIMPs) are involved in remodeling the extracellular matrix. Amyloid beta-42 interrupts the integrity of the neurovascular unit and induces a toxic reaction affecting neurons. Objective: This study investigated the relationships among genetic variants of the MMP-2, MMP-9, TIMP-1, and TIMP-2 genes and AD. Methods: Two hundred and thirteen probable AD patients and 315 control participants of the Tai- wan population were recruited for primary investigations, and we used the data of 763 participants from the Taiwan Biobank (TWB), as controls, for validation. Multivariable logistic regression was performed with adjustments for age, sex, hypertension, diabetes mellitus (DM), and alcohol con- sumption. The associations between the genotypes and allele frequencies and the SNP-associated AD hereditary models were analyzed using the SNPassoc package for R. We performed a permuta- tion test with 1,000 replicates for the empirical estimates. Results: A total of 213 probable AD patients and 315 control participants were recruited. The fre- quency of the A alleles in rs7503726 (G > A) in TIMP-2 was lower in the AD patients (p < 0.01). The frequencies of the TIMP-2 rs7503726 G/A and A/A genotypes were also significantly lower in the AD patients (p = 0.02) than in the controls and TWB. The TIMP-2 rs7503726 AA genotype was associated with a protective effect of AD in additive and recessive hereditary models (OR = 0.54, 95% CI: 0.32 – 0.92, p = 0.02; OR = 0.68, 95% CI: 0.50 – 0.92, p = 0.01, respectively). Conclusion: The TIMP-2 rs7503726 AA genotype was inversely correlated with AD susceptibili- ty, and the presence of minor alleles of rs7503726 (A allele) have protective effects against AD.

MicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms

2018 ◽  
Vol 29 (2) ◽  
pp. 161-182 ◽  
Author(s):  
Reihaneh Dehghani ◽  
Farzaneh Rahmani ◽  
Nima Rezaei
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Neural Plasticity ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Active Role ◽  
Search Term ◽  
The Central Nervous System ◽  
Irregular Cell

AbstractPathology of Alzheimer’s disease (AD) goes far beyond neurotoxicity resulting from extracellular deposition of amyloid β (Aβ) plaques. Aberrant cleavage of amyloid precursor protein and accumulation of Aβ in the form of the plaque or neurofibrillary tangles are the known primary culprits of AD pathogenesis and target for various regulatory mechanisms. Hyper-phosphorylation of tau, a major component of neurofibrillary tangles, precipitates its aggregation and prevents its clearance. Lipid particles, apolipoproteins and lipoprotein receptors can act in favor or against Aβ and tau accumulation by altering neural membrane characteristics or dynamics of transport across the blood-brain barrier. Lipids also alter the oxidative/anti-oxidative milieu of the central nervous system (CNS). Irregular cell cycle regulation, mitochondrial stress and apoptosis, which follow both, are also implicated in AD-related neuronal loss. Dysfunction in synaptic transmission and loss of neural plasticity contribute to AD. Neuroinflammation is a final trail for many of the pathologic mechanisms while playing an active role in initiation of AD pathology. Alterations in the expression of microRNAs (miRNAs) in AD and their relevance to AD pathology have long been a focus of interest. Herein we focused on the precise pathomechanisms of AD in which miRNAs were implicated. We performed literature search through PubMed and Scopus using the search term: (‘Alzheimer Disease’) OR (‘Alzheimer’s Disease’) AND (‘microRNAs’ OR ‘miRNA’ OR ‘MiR’) to reach for relevant articles. We show how a limited number of common dysregulated pathways and abnormal mechanisms are affected by various types of miRNAs in AD brain.

scholarly journals Liraglutide and its Neuroprotective Properties—Focus on Possible Biochemical Mechanisms in Alzheimer’s Disease and Cerebral Ischemic Events

2019 ◽  
Vol 20 (5) ◽  
pp. 1050 ◽  
Author(s):  
Michał Wiciński ◽  
Maciej Socha ◽  
Bartosz Malinowski ◽  
Eryk Wódkiewicz ◽  
Maciej Walczak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radicals ◽  
Neuronal Damage ◽  
Neurovascular Unit ◽  
Neurological Deficits ◽  
Intercellular Adhesion Molecule ◽  
Aβ Amyloid ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Liraglutide is a GLP-1 analog (glucagon like peptide-1) used primarily in the treatment of diabetes mellitus type 2 (DM2) and obesity. The literature starts to suggest that liraglutide may reduce the effects of ischemic stroke by activating anti-apoptotic pathways, as well as limiting the harmful effects of free radicals. The GLP-1R expression has been reported in the cerebral cortex, especially occipital and frontal lobes, the hypothalamus, and the thalamus. Liraglutide reduced the area of ischemia caused by MCAO (middle cerebral artery occlusion), limited neurological deficits, decreased hyperglycemia caused by stress, and presented anti-apoptotic effects by increasing the expression of Bcl-2 and Bcl-xl proteins and reduction of Bax and Bad protein expression. The pharmaceutical managed to decrease concentrations of proapoptotic factors, such as NF-κB (Nuclear Factor-kappa β), ICAM-1 (Intercellular Adhesion Molecule 1), caspase-3, and reduced the level of TUNEL-positive cells. Liraglutide was able to reduce the level of free radicals by decreasing the level of malondialdehyde (MDA), and increasing the superoxide dismutase level (SOD), glutathione (GSH), and catalase. Liraglutide may affect the neurovascular unit causing its remodeling, which seems to be crucial for recovery after stroke. Liraglutide may stabilize atherosclerotic plaque, as well as counteract its early formation and further development. Liraglutide, through its binding to GLP-1R (glucagon like peptide-1 receptor) and consequent activation of PI3K/MAPK (Phosphoinositide 3-kinase/mitogen associated protein kinase) dependent pathways, may have a positive impact on Aβ (amyloid beta) trafficking and clearance by increasing the presence of Aβ transporters in cerebrospinal fluid. Liraglutide seems to affect tau pathology. It is possible that liraglutide may have some stem cell stimulating properties. The effects may be connected with PKA (phosphorylase kinase A) activation. This paper presents potential mechanisms of liraglutide activity in conditions connected with neuronal damage, with special emphasis on Alzheimer’s disease and cerebral ischemia.

scholarly journals Ficus Erecta Thunb. Leaves Protect Against Cognitive Deficit and Neuronal Damage in a Mouse Model of Amyloid-β-induced Alzheimer’s Disease

2020 ◽  
Author(s):  
Eunjin Sohn ◽  
Yu Jin Kim ◽  
Joo-Hwan Kim ◽  
Soo-Jin Jeong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Inflammatory Cytokines ◽  
Cognitive Deficit ◽  
Neuronal Damage ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Bdnf Signaling ◽  
Brain Tissues

Abstract Background: Alzheimer’s disease (AD) pathogenesis is linked to amyloid plaque accumulation, neuronal loss, and brain inflammation. Ficus erecta Thunb. is a food and medicinal plant used to treat inflammatory diseases. Methods: we investigated the neuroprotective effects of F. erecta Thunb. against cognitive deficit and neuronal damage in a mouse model of amyloid-β (Aβ)-induced AD. Results: First, we confirmed the inhibitory effects of ethanol extracts of F. erecta (EEFE) leaves on Aβ aggregation in vivo and in vitro. Next, behavioral tests (passive avoidance task and Morris water maze) revealed EEFE markedly improved cognitive impairment in Aβ-injected mice. Furthermore, EEFE reduced neuronal loss and the expression of neuronal nuclei (NeuN), a neuronal marker, in brain tissues of Aβ-injected mice. EEFE significantly reversed Aβ-induced suppression of cAMP response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression, indicating neuroprotection was mediated by CREB/BDNF signaling. Moreover, EEFE significantly suppressed the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and expression of ionized calcium-binding adaptor molecule 1 (Iba-1), a marker of microglial activation, in brain tissues of Aβ-injected mice, suggesting anti-neuroinflammatory effects. Conclusions: Taken together, EEFE protected against cognitive deficit and neuronal damage in AD-like mice via activation of CREB/BDNF signaling and upregulation of inflammatory cytokines.

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