scholarly journals Targeting Galectin 3 to Counteract Spike-Phase Uncoupling of Fast-Spiking Interneurons to Gamma Oscillations in Alzheimer’s Disease

2021 ◽  
Author(s):  
Luis Enrique Arroyo-García ◽  
Sara Bachiller ◽  
Antonio Boza-Serrano ◽  
Antonio Rodríguez-Moreno ◽  
Tomas Deierborg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Network ◽  
Neurodegenerative Disorder ◽  
Network Dynamics ◽  
Gamma Oscillations ◽  
Dependent Manner ◽  
Galectin 3 ◽  
Fast Spiking ◽  
5Xfad Mice

Abstract Background: Alzheimer’s disease (AD) is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists. Neuroinflammation is central to the pathology progression, with evidence suggesting that microglia-released galectin 3 (gal3) plays a pivotal role by amplifying neuroinflammation in AD. However, possible involvement of gal3 in the disruption of cognition-relevant neuronal network oscillations typical of AD remains unknown. Methods: Here, we investigate the functional implications of gal3 signaling on cognition-relevant gamma oscillations (30-80 Hz) by performing electrophysiological recordings in hippocampal area CA3 of wild-type (WT) and 5xFAD mice in vitro. Results: Gal3 application decreases gamma oscillation power and rhythmicity in an activity-dependent manner and is accompanied by impairment of cellular dynamics in fast-spiking interneurons (FSN) and pyramidal cells (PCs). We found that gal3-induced disruption is mediated by the gal3-carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139, which also prevents Aβ42-induced degradation of gamma oscillations. Furthermore, we demonstrate that 5xFAD mice lacking gal3 (5xFAD-Gal3KO) exhibit WT-like gamma network dynamics.Conclusions: We report for the first time that gal3 impairs cognition-relevant neuronal network dynamics by spike-phase uncoupling of FSN inducing a network performance collapse. Moreover, our findings suggest gal3 inhibition as a potential therapeutic target to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.

scholarly journals Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the AppNL-G-F mouse model of Alzheimer’s disease

2021 ◽  
Author(s):  
Luis Enrique Arroyo-García ◽  
Arturo G. Isla ◽  
Yuniesky Andrade-Talavera ◽  
Hugo Balleza-Tapia ◽  
Raúl Loera-Valencia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mouse Model ◽  
Functional Impairment ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Gamma Oscillation ◽  
Gamma Rhythm ◽  
Fast Spiking

AbstractIn Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.

scholarly journals Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer’s disease pathology

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Caroline A. Wilson ◽  
Sarah Fouda ◽  
Shuzo Sakata
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Basal Forebrain ◽  
Gamma Oscillations ◽  
Cortical Region ◽  
Sensory Stimuli ◽  
Beneficial Effects ◽  
Amyloid Load ◽  
5Xfad Mice ◽  
Frontal Cortical Region

Abstract Neuronal activity can modify Alzheimer’s disease pathology. Overexcitation of neurons can facilitate disease progression whereas the induction of cortical gamma oscillations can reduce amyloid load and improve cognitive functions in mouse models. Although previous studies have induced cortical gamma oscillations by either optogenetic activation of cortical parvalbumin-positive (PV+) neurons or sensory stimuli, it is still unclear whether other approaches to induce gamma oscillations can also be beneficial. Here we show that optogenetic activation of PV+ neurons in the basal forebrain (BF) increases amyloid burden, rather than reducing it. We applied 40 Hz optical stimulation in the BF by expressing channelrhodopsin-2 (ChR2) in PV+ neurons of 5xFAD mice. After 1-h induction of cortical gamma oscillations over three days, we observed the increase in the concentration of amyloid-β42 in the frontal cortical region, but not amyloid-β40. Amyloid plaques were accumulated more in the medial prefrontal cortex and the septal nuclei, both of which are targets of BF PV+ neurons. These results suggest that beneficial effects of cortical gamma oscillations on Alzheimer’s disease pathology can depend on the induction mechanisms of cortical gamma oscillations.

scholarly journals Altered Theta Oscillations and Aberrant Cortical Excitatory Activity in the 5XFAD Model of Alzheimer’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Magdalena Elisabeth Siwek ◽  
Ralf Müller ◽  
Christina Henseler ◽  
Astrid Trog ◽  
Andreas Lundt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Cortical Excitability ◽  
Theta Oscillations ◽  
Dark Phase ◽  
Model Of Alzheimer’S Disease ◽  
Cortical Hyperexcitability ◽  
5Xfad Mice ◽  
Hippocampal Theta

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by impairment of memory function. The 5XFAD mouse model was analyzed and compared with wild-type (WT) controls for aberrant cortical excitability and hippocampal theta oscillations by using simultaneous video-electroencephalogram (EEG) monitoring. Seizure staging revealed that 5XFAD mice exhibited cortical hyperexcitability whereas controls did not. In addition, 5XFAD mice displayed a significant increase in hippocampal theta activity from the light to dark phase during nonmotor activity. We also observed a reduction in mean theta frequency in 5XFAD mice compared to controls that was again most prominent during nonmotor activity. Transcriptome analysis of hippocampal probes and subsequent qPCR validation revealed an upregulation of Plcd4 that might be indicative of enhanced muscarinic signalling. Our results suggest that 5XFAD mice exhibit altered cortical excitability, hippocampal dysrhythmicity, and potential changes in muscarinic signaling.

scholarly journals Gamma Oscillations in Alzheimer’s Disease and Their Potential Therapeutic Role

2021 ◽  
Vol 15 ◽  
Author(s):  
Artemis Traikapi ◽  
Nikos Konstantinou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Potential Role ◽  
Neurodegenerative Disorder ◽  
Brain Activity ◽  
Sensory Stimulation ◽  
Gamma Oscillations ◽  
Potential Therapeutic Role ◽  
Modifying Effect

Despite decades of research, Alzheimer’s Disease (AD) remains a lethal neurodegenerative disorder for which there are no effective treatments. This review examines the latest evidence of a novel and newly introduced perspective, which focuses on the restoration of gamma oscillations and investigates their potential role in the treatment of AD. Gamma brain activity (∼25–100 Hz) has been well-known for its role in cognitive function, including memory, and it is fundamental for healthy brain activity and intra-brain communication. Aberrant gamma oscillations have been observed in both mice AD models and human AD patients. A recent line of work demonstrated that gamma entrainment, through auditory and visual sensory stimulation, can effectively attenuate AD pathology and improve cognitive function in mice models of the disease. The first evidence from AD patients indicate that gamma entrainment therapy can reduce loss of functional connectivity and brain atrophy, improve cognitive function, and ameliorate several pathological markers of the disease. Even though research is still in its infancy, evidence suggests that gamma-based therapy may have a disease-modifying effect and has signified a new and promising era in AD research.

scholarly journals Synaptic Plasticity and Oscillations in Alzheimer’s Disease: A Complex Picture of a Multifaceted Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Yuniesky Andrade-Talavera ◽  
Antonio Rodríguez-Moreno
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Neuronal Network ◽  
Brain Plasticity ◽  
Network Dynamics ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Neuronal Network Dynamics

Brain plasticity is widely accepted as the core neurophysiological basis of memory and is generally defined by activity-dependent changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). By using diverse induction protocols like high-frequency stimulation (HFS) or spike-timing dependent plasticity (STDP), such crucial cognition-relevant plastic processes are shown to be impaired in Alzheimer’s disease (AD). In AD, the severity of the cognitive impairment also correlates with the level of disruption of neuronal network dynamics. Currently under debate, the named amyloid hypothesis points to amyloid-beta peptide 1–42 (Aβ42) as the trigger of the functional deviations underlying cognitive impairment in AD. However, there are missing functional mechanistic data that comprehensively dissect the early subtle changes that lead to synaptic dysfunction and subsequent neuronal network collapse in AD. The convergence of the study of both, mechanisms underlying brain plasticity, and neuronal network dynamics, may represent the most efficient approach to address the early triggering and aberrant mechanisms underlying the progressive clinical cognitive impairment in AD. Here we comment on the emerging integrative roles of brain plasticity and network oscillations in AD research and on the future perspectives of research in this field.

scholarly journals Altered Brain Leptin and Leptin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease

2020 ◽  
Vol 13 (11) ◽  
pp. 401
Author(s):  
Anishchal A. Pratap ◽  
R. M. Damian Holsinger
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Leptin Receptor ◽  
Neurodegenerative Disorder ◽  
Receptor Expression ◽  
Immunofluorescent Staining ◽  
5Xfad Mouse ◽  
5Xfad Mice ◽  
Lepr Expression

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Interestingly, individuals with metabolic syndromes share some pathologies with those diagnosed with AD including neuroinflammation, insulin resistance and cognitive deficits. Leptin, an adipocyte-derived hormone, regulates metabolism, energy expenditure and satiety via its receptor, LepR. To investigate the possible involvement of leptin in AD, we examined the distribution of leptin and LepR in the brains of the 5XFAD mouse model of AD, utilizing immunofluorescent staining in young (10–12-weeks; n = 6) and old (48–52-weeks; n = 6) transgenic (Tg) mice, together with age-matched wild-type (WT) controls for both age groups (young-WT, n = 6; old-WT, n = 6). We also used double immunofluorescent staining to examine the distribution of leptin and leptin receptor expression in astrocytes. In young 5XFAD, young-WT and old-WT mice, we observed neuronal and endothelial expression of leptin and LepR throughout the brain. However, neuronal leptin and LepR expression in the old 5XFAD brain was significantly diminished. Reduced neuronal leptin and LepR expression was accompanied by plaque loading and neuroinflammation in the AD brain. A marked increase in astrocytic leptin and LepR was also observed in old 5XFAD mice compared to younger 5XFAD mice. We postulate that astrocytes may utilize LepR signalling to mediate and drive their metabolically active state when degrading amyloid in the AD brain. Overall, these findings provide evidence of impaired leptin and LepR signalling in the AD brain, supporting clinical and epidemiological studies performed in AD patients.

scholarly journals Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity

2019 ◽  
Author(s):  
Shoshik Amram ◽  
Tal Iram ◽  
Ekaterina Lazdon ◽  
Robert Vassar ◽  
Ittai Ben-Porath ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cellular Senescence ◽  
Amyloid Β ◽  
Dependent Manner ◽  
Inflammatory Phenotype ◽  
Secretory Phenotype ◽  
5Xfad Mice ◽  
Tgf Β1

ABSTRACTAlterations in astrocyte function such as a pro-inflammatory phenotype are associated with Alzheimer’s disease (AD). We had shown impairments in the ability of aged astrocytes isolated from 5xFAD mice to clear and uptake amyloid-β (Aβ) as well as to support neuronal growth. Senescent cells accumulate with age and exhibit a senescence-associated secretory phenotype, which includes secretion of pro-inflammatory cytokines. In this study, we predicted that with age, astrocytes in 5xFAD mice would exhibit a cellular senescence phenotype that could promote neurodegeneration. We found an age-dependent increase in senescent astrocytes adjacent to Aβ plaques in 5xFAD mice. Inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells reduced interelukin-6 secretion by senescent astrocytes and resulted in improved neuronal support. Moreover, senescent astrocytes exhibited an increase in the induction of the TGF-β1-SMAD2/3 pathway, and inhibition of this pathway resulted in a reduction of cellular senescence. We also discovered that soluble Aβ42 induced astrocyte senescence in young naïve mice in a SMAD2/3-dependent manner. Our results suggest an important role of astrocyte senescence in AD and its role in mediating the neurotoxicity properties of astrocytes in AD and related neurodegenerative diseases.

scholarly journals Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

2020 ◽  
Vol 21 (3) ◽  
pp. 1144
Author(s):  
Ariel Angel ◽  
Rotem Volkman ◽  
Tabitha Grace Royal ◽  
Daniel Offen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Cysteine Proteases ◽  
Knock Out ◽  
Model Of Alzheimer’S Disease ◽  
Caspase 6 ◽  
5Xfad Mice

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-β plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD.

scholarly journals Inhibitory Neural Network’s Impairments at Hippocampal CA1 LTP in an Aged Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (2) ◽  
pp. 698
Author(s):  
Hyeon Jeong Seo ◽  
Jung Eun Park ◽  
Seong-Min Choi ◽  
Taekyoung Kim ◽  
Soo Hyun Cho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Signal Transmission ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Long Term Potentiation ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
The Impact

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid β (Aβ) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.

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