scholarly journals Alzheimer′s brain inoculation in Aβ-plaque bearing mice: synaptic loss is linked to tau seeding and low microglial activity

2021 ◽  
Author(s):  
Suzanne Lam ◽  
Susana Boluda ◽  
Anne Sophie Herard ◽  
Fanny Petit ◽  
Sabiha Eddarkaoui ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Genetic Manipulation ◽  
Cognitive Impairments ◽  
Amyloid Β ◽  
Intracerebral Injection ◽  
Neuritic Plaques ◽  
Synaptic Loss ◽  
Brain Extracts ◽  
Amyloid Load ◽  
The Brain

Alzheimer's disease (AD) is characterized by synaptic alterations that lead to cognitive impairments and by a number of lesions including extracellular amyloid–β (Aβ) plaques, intracellular tau accumulation and neuroinflammation. The contribution of these lesions to synaptic alterations is still debated. Through the intracerebral injection of human AD brain extracts into an Aβ plaque–bearing mouse model that does not overexpress tau we recapitulated all these AD lesions. In particular neuritic plaques, AD-like neurofibrillary tangles and neuropil threads, that spread through the brain, were identified and characterized. Interestingly neuritic plaques but not other tau-positive lesions were observed in control-inoculated animals as well as in non-inoculated amyloid-bearing mice, suggesting that these lesions do not require exogeneous tau to be initiated. Inoculation of different human AD brain extracts to mice led to lesional heterogeneity and to enhanced synaptic loss and cognitive impairments. Relationships between synaptic alterations or cognitive impairments and AD pathology were evaluated by exploiting the induced lesional heterogeneity. Synaptic loss and cognitive deficits were associated with the severity of tau lesions and to lower microglial load, but not to amyloid load. Our results outline that new mouse models of AD bearing both Aβ plaques and tau lesions, and based on AD brain extracts inoculation, allow to investigate AD neurodegenerative processes. They highlight the contribution of tau to synaptic impairments in a model that does not rely on genetic manipulation of tau protein and indicate that microglial activity may protect against synaptic loss.

scholarly journals Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3261
Author(s):  
Xiao Liu ◽  
Qian Zhou ◽  
Jia-He Zhang ◽  
Xiaoying Wang ◽  
Xiumei Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Disease Model ◽  
Amyloid Β ◽  
Brain Lesions ◽  
Synaptic Dysfunction ◽  
Synaptic Loss ◽  
And Function ◽  
The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

Immunization of Alzheimer model mice with adenovirus vectors encoding amyloid β-protein and GM-CSF reduces amyloid load in the brain

2004 ◽  
Vol 370 (2-3) ◽  
pp. 218-223 ◽  
Author(s):  
Hong-Duck Kim ◽  
Fan-Kun Kong ◽  
Yunpeng Cao ◽  
Terry L. Lewis ◽  
Helen Kim ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Gm Csf ◽  
Β Protein ◽  
Amyloid Load ◽  
Adenovirus Vectors ◽  
The Brain

scholarly journals URMC-099 Prophylaxis Repairs Hippocampal Vascular Damage in an Orthopedic Model of Delirium Superimposed on Dementia

2021 ◽  
Author(s):  
Patrick Miller-Rhodes ◽  
Herman Li ◽  
Ravikanth Velagapudi ◽  
Niccolo Terrando ◽  
Harris A Gelbard
Keyword(s):  
Cognitive Deficits ◽  
Microglial Activation ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Endothelial Activation ◽  
Surgical Trauma ◽  
Data Link ◽  
Synapse Loss ◽  
The Brain ◽  
Delirium Superimposed On Dementia

Systemic perturbations can drive a neuroimmune cascade after surgical trauma, including affecting the blood-brain barrier (BBB), activating microglia, and contributing to cognitive deficits such as delirium. Delirium superimposed on dementia (DSD) is a particularly debilitating complication that renders the brain further vulnerable to neuroinflammation and neurodegeneration, albeit these molecular mechanisms remain poorly understood. Here we have used an orthopedic model of tibial fracture/fixation in APPSwDI/mNos2-/- AD (CVN-AD) mice to investigate relevant pathogenetic mechanisms underlying DSD. We conducted the present study in 6 months-old CVN-AD mice, an age at which we speculated amyloid-β pathology had not saturated BBB and neuroimmune functioning. We found that URMC-099, our brain-penetrant anti-inflammatory neuroprotective drug, prevented inflammatory endothelial activation, synapse loss, and microglial activation in our DSD model. Taken together, our data link post-surgical endothelial activation, microglial MafB immunoreactivity, and synapse loss as key substrates for DSD, all of which can be reversed by URMC-099.

scholarly journals In Search of Molecular Markers for Cerebellar Neurons

2021 ◽  
Vol 22 (4) ◽  
pp. 1850
Author(s):  
Wing Yip Tam ◽  
Xia Wang ◽  
Andy S. K. Cheng ◽  
Kwok-Kuen Cheung
Keyword(s):  
Cognitive Deficits ◽  
Motor Coordination ◽  
Normal Development ◽  
Genetic Manipulation ◽  
Cell Types ◽  
Functional Study ◽  
Cerebellar Neurons ◽  
The Brain ◽  
Neuronal Type

The cerebellum, the region of the brain primarily responsible for motor coordination and balance, also contributes to non-motor functions, such as cognition, speech, and language comprehension. Maldevelopment and dysfunction of the cerebellum lead to cerebellar ataxia and may even be associated with autism, depression, and cognitive deficits. Hence, normal development of the cerebellum and its neuronal circuitry is critical for the cerebellum to function properly. Although nine major types of cerebellar neurons have been identified in the cerebellar cortex to date, the exact functions of each type are not fully understood due to a lack of cell-specific markers in neurons that renders cell-specific labeling and functional study by genetic manipulation unfeasible. The availability of cell-specific markers is thus vital for understanding the role of each neuronal type in the cerebellum and for elucidating the interactions between cell types within both the developing and mature cerebellum. This review discusses various technical approaches and recent progress in the search for cell-specific markers for cerebellar neurons.

scholarly journals Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Jia ◽  
Juan Piña-Crespo ◽  
Yonghe Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Signal Transduction Pathway ◽  
Amyloid Β ◽  
Synaptic Loss ◽  
Cellular Processes ◽  
And Function ◽  
The Brain ◽  
Blood Brain Barrier Integrity

AbstractAlzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling is an essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, Wnt/β-catenin signaling is not only crucial for neuronal survival and neurogenesis, but it plays important roles in regulating synaptic plasticity and blood-brain barrier integrity and function. Moreover, activation of Wnt/β-catenin signaling inhibits amyloid-β production and tau protein hyperphosphorylation in the brain. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brain via multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for the rational design of novel AD therapies.

scholarly journals EXTH-08. REPLACEMENT OF MICROGLIA BY BRAIN-ENGRAFTED MACROPHAGES PREVENTS MEMORY DEFICITS AFTER THERAPEUTIC WHOLE-BRAIN IRRADIATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi83-vi84
Author(s):  
Xi Feng ◽  
Sonali Gupta ◽  
David Chen ◽  
Zoe Boosalis ◽  
Sharon Liu ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Memory Deficits ◽  
Protective Effects ◽  
Whole Brain Irradiation ◽  
Synaptic Loss ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy ◽  
The Brain ◽  
Therapeutic Avenue

Abstract Microglia have a distinct origin compared to blood circulating myeloid cells. Under normal physiological conditions, microglia are maintained by self-renewal, independent of hematopoietic progenitors. Following genetic or pharmacologic depletion, newborn microglia derive from the local residual pool and quickly repopulate the entire brain. The depletion of brain resident microglia during therapeutic whole-brain irradiation fully prevents irradiation-induced synaptic loss and recognition memory deficits but the mechanisms driving these protective effects are unknown. Here, we demonstrate that after CSF-1R inhibitor-mediated microglia depletion and therapeutic whole-brain irradiation, circulating monocytes engraft into the brain and replace the microglia pool. These monocyte-derived brain-engrafted macrophages have reduced phagocytic activity compared to microglia from irradiated brains, but similar to locally repopulated microglia without brain irradiation. Transcriptome comparisons reveal that brain-engrafted macrophages have both monocyte and embryonic microglia signatures. These results suggest that monocyte-derived brain-engrafted macrophages represent a novel therapeutic avenue for the treatment of brain radiotherapy-induced cognitive deficits.

scholarly journals Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

2020 ◽  
Author(s):  
Dongdong Zhang ◽  
Sheng Li ◽  
Liyan Hou ◽  
Lu Jing ◽  
Zhengzheng Ruan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cognitive Decline ◽  
Passive Avoidance ◽  
Cognitive Performance ◽  
Cognitive Deficits ◽  
Water Maze ◽  
Microglial Activation ◽  
Cognitive Impairments ◽  
Synaptic Loss

Abstract BackgroundCognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the life quality of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by over-activated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using rotenone-induced mouse PD model. Methods: To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by morris water maze, objective recognition and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation and apoptosis were determined by immunohistochemistry, Western blot or immunofluorescence staining. The gene expressions of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased abilities of novel objective recognition, passive avoidance, as well as morris water maze performance compared with vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. Time course study revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 or minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in combined PLX3397 or minocycline and rotenone-treated mice compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. ConclusionsTaken together, our findings suggested that microglial activation contributed to cognitive impairments in rotenone-induced mouse PD model via neuroinflammation, oxidative stress and apoptosis, providing novel insight for the immunopathogensis of cognitive deficits in PD.

scholarly journals Astrocyte-derived clusterin suppresses amyloid formation in vivo

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aleksandra M. Wojtas ◽  
Jonathon P. Sens ◽  
Silvia S. Kang ◽  
Kelsey E. Baker ◽  
Taylor J. Berry ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Amyloid Formation ◽  
Plaque Load ◽  
Amyloid Load ◽  
Or Gene ◽  
And Control ◽  
The Brain

Abstract Background Accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer’s disease (AD). The clusterin (CLU) gene confers a risk for AD and CLU is highly upregulated in AD patients, with the common non-coding, protective CLU variants associated with increased expression. Although there is strong evidence implicating CLU in amyloid metabolism, the exact mechanism underlying the CLU involvement in AD is not fully understood or whether physiologic alterations of CLU levels in the brain would be protective. Results We used a gene delivery approach to overexpress CLU in astrocytes, the major source of CLU expression in the brain. We found that CLU overexpression resulted in a significant reduction of total and fibrillar amyloid in both cortex and hippocampus in the APP/PS1 mouse model of AD amyloidosis. CLU overexpression also ameliorated amyloid-associated neurotoxicity and gliosis. To complement these overexpression studies, we also analyzed the effects of haploinsufficiency of Clu using heterozygous (Clu+/−) mice and control littermates in the APP/PS1 model. CLU reduction led to a substantial increase in the amyloid plaque load in both cortex and hippocampus in APP/PS1; Clu+/− mice compared to wild-type (APP/PS1; Clu+/+) littermate controls, with a concomitant increase in neuritic dystrophy and gliosis. Conclusions Thus, both physiologic ~ 30% overexpression or ~ 50% reduction in CLU have substantial impacts on amyloid load and associated pathologies. Our results demonstrate that CLU plays a major role in Aβ accumulation in the brain and suggest that efforts aimed at CLU upregulation via pharmacological or gene delivery approaches offer a promising therapeutic strategy to regulate amyloid pathology.

scholarly journals SAK3 Administration Improves Spine Abnormalities and Cognitive Deficits in AppNL-G-F/NL-G-F Knock-in Mice by Increasing Proteasome Activity through CaMKII/Rpt6 Signaling

2020 ◽  
Vol 21 (11) ◽  
pp. 3833 ◽  
Author(s):  
Hisanao Izumi ◽  
Ichiro Kawahata ◽  
Yasuharu Shinoda ◽  
Fred J. Helmstetter ◽  
Kohji Fukunaga
Keyword(s):  
Signaling Pathway ◽  
Cognitive Deficits ◽  
Neurofibrillary Tangles ◽  
Cognitive Impairments ◽  
Amyloid Β ◽  
Proteasome Activity ◽  
Drug Candidate ◽  
Therapeutic Effects ◽  
Detailed Mechanism ◽  
Spine Abnormalities

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by neuropathological hallmarks consisting of accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFT). Recently, we have identified a new AD therapeutic candidate, ethyl-8′-methyl-2′,4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1,3′-imidazo [1,2-a] pyridin]-2-ene-3-carboxylate (SAK3), which ameliorates the AD-like pathology in AppNL-F/NL-F knock-in mice. However, the detailed mechanism underlying the therapeutic effects of SAK3 remains unclear. In this study, we found that SAK3 administration improved the reduced proteasome activity through the activation of CaMKII/Rpt6 signaling in AppNL-F/NL-F knock-in (NL-G-F) mice. Moreover, spine abnormalities observed in NL-G-F mice were significantly reversed by SAK3 administration. Along with this, cognitive impairments found in NL-G-F mice were markedly ameliorated by SAK3. In summary, our data suggest that SAK3 administration increases the activity of the proteasome via activation of the CaMKII/Rpt6 signaling pathway, contributing to improvements in spine abnormalities and cognitive deficits in NL-G-F mice. Overall, our findings suggest that SAK3 might be a new attractive drug candidate, representing a new mechanism for the treatment of AD pathology.

scholarly journals A Standardized Extract of Asparagus officinalis Stem (ETAS®) Ameliorates Cognitive Impairment, Inhibits Amyloid β Deposition via BACE-1 and Normalizes Circadian Rhythm Signaling via MT1 and MT2

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1631
Author(s):  
Yin-Ching Chan ◽  
Ci-Sian Wu ◽  
Tsai-Chen Wu ◽  
Yu-Hsuan Lin ◽  
Sue-Joan Chang
Keyword(s):  
Circadian Rhythm ◽  
Cognitive Impairments ◽  
Amyloid Β ◽  
The Elderly ◽  
Asparagus Officinalis ◽  
Melatonin Receptor ◽  
Bioactive Constituents ◽  
The Brain ◽  
Senescence Accelerated Mice ◽  
Bace 1

The prevalence of cognitive impairments and circadian disturbances increases in the elderly and Alzheimer’s disease (AD) patients. This study investigated the effects of a standardized extract of Asparagus officinalis stem, ETAS® on cognitive impairments and circadian rhythm status in senescence-accelerated mice prone 8 (SAMP8). ETAS® consists of two major bioactive constituents: 5-hydroxymethyl-2-furfural (HMF), an abundant constituent, and (S)-asfural, a novel constituent, which is a derivative of HMF. Three-month-old SAMP8 male mice were divided into a control, 200 and 1000 mg/kg BW ETAS® groups, while senescence-accelerated resistant mice (SAMR1) were used as the normal control. After 12-week feeding, ETAS® significantly enhanced cognitive performance by an active avoidance test, inhibited the expressions of amyloid-beta precursor protein (APP) and BACE-1 and lowered the accumulation of amyloid β (Aβ) in the brain. ETAS® also significantly increased neuron number in the suprachiasmatic nucleus (SCN) and normalized the expressions of the melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). In conclusion, ETAS® enhances the cognitive ability, inhibits Aβ deposition and normalizes circadian rhythm signaling, suggesting it is beneficial for preventing cognitive impairments and circadian rhythm disturbances in aging.

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