scholarly journals Anti-inflammatory treatment with FTY720 starting after onset of symptoms reverses synaptic and memory deficits in an AD mouse model

2019 ◽  
Author(s):  
Georgia-Ioanna Kartalou ◽  
Ana Rita Salgueiro Pereira ◽  
Thomas Endres ◽  
Angelina Lesnikova ◽  
Plinio Casarotto ◽  
...  
Keyword(s):  
Mouse Model ◽  
Pyramidal Neurons ◽  
Memory Performance ◽  
Disease Onset ◽  
Immunohistochemical Analysis ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Disease Symptoms ◽  
Approved Drugs ◽  
Ad Mouse Model

AbstractTherapeutical approaches providing effective medication for Alzheimer’s disease (AD) patients after disease onset are urgently needed. Repurposing FDA approved drugs like fingolimod (FTY720) for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms. Here, we addressed whether the FDA approved drug fingolimod rescues AD related synaptic deficits and memory dysfunction in an APP/PS1 AD mouse model when medication starts after onset of symptoms (at 5 months). Male mice received intraperitoneal injections of fingolimod for 1-2 months starting at 5-6 months. This treatment rescued spine density as well as long-term potentiation in hippocampal CA1 pyramidal neurons, and ameliorated dysfunctional hippocampus-dependent memory that was observed in untreated APP/PS1 animals at 6-7 months of age. Immunohistochemical analysis with markers of microgliosis (Iba1) and astrogliosis (GFAP) revealed that our fingolimod treatment regime strongly down regulated neuro-inflammation in the hippocampus and cortex of this AD model. These effects were accompanied by a moderate reduction of Aβ accumulation in hippocampus and cortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology and related memory performance deficits observed in untreated AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.

scholarly journals Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model

2020 ◽  
Vol 21 (23) ◽  
pp. 8957
Author(s):  
Georgia-Ioanna Kartalou ◽  
Ana Rita Salgueiro-Pereira ◽  
Thomas Endres ◽  
Angelina Lesnikova ◽  
Plinio Casarotto ◽  
...  
Keyword(s):  
Mouse Model ◽  
Calcium Binding ◽  
Disease Onset ◽  
Memory Deficits ◽  
Long Term Potentiation ◽  
Glial Fibrillary Acid Protein ◽  
Spine Density ◽  
Disease Symptoms ◽  
Multiple Sclerosis Patients ◽  
Ad Mouse Model

Therapeutic approaches providing effective medication for Alzheimer’s disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of Aβ accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.

scholarly journals Torpor enhances synaptic strength and restores memory performance in a mouse model of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christina F. de Veij Mestdagh ◽  
Jaap A. Timmerman ◽  
Frank Koopmans ◽  
Iryna Paliukhovich ◽  
Suzanne S. M. Miedema ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Memory Performance ◽  
Long Term Potentiation ◽  
Fear Memory ◽  
Contextual Fear ◽  
Contextual Fear Memory ◽  
Model Of Alzheimer’S Disease ◽  
Term Potentiation

AbstractHibernation induces neurodegeneration-like changes in the brain, which are completely reversed upon arousal. Hibernation-induced plasticity may therefore be of great relevance for the treatment of neurodegenerative diseases, but remains largely unexplored. Here we show that a single torpor and arousal sequence in mice does not induce dendrite retraction and synapse loss as observed in seasonal hibernators. Instead, it increases hippocampal long-term potentiation and contextual fear memory. This is accompanied by increased levels of key postsynaptic proteins and mitochondrial complex I and IV proteins, indicating mitochondrial reactivation and enhanced synaptic plasticity upon arousal. Interestingly, a single torpor and arousal sequence was also sufficient to restore contextual fear memory in an APP/PS1 mouse model of Alzheimer’s disease. Our study demonstrates that torpor in mice evokes an exceptional state of hippocampal plasticity and that naturally occurring plasticity mechanisms during torpor provide an opportunity to identify unique druggable targets for the treatment of cognitive impairment.

scholarly journals IL-37 expression reduces acute and chronic neuroinflammation and rescues cognitive impairment in an Alzheimer s disease mouse model

2021 ◽  
Author(s):  
Niklas Lonnemann ◽  
Shirin Hosseini ◽  
Melanie Ohm ◽  
Karsten Hiller ◽  
Charles A. Dinarello ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cognitive Abilities ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Chronic Neuroinflammation ◽  
Model Of Alzheimer’S Disease ◽  
Term Potentiation ◽  
Anti Inflammatory ◽  
And Function ◽  
And Behavior

The anti-inflammatory cytokine interleukin-37 (IL-37) is a member of the IL-1 family but not expressed in mice. We used a human IL 37 (hIL-37tg) expressing mouse, which has been subjected to various models of local and systemic inflammation as well as immunological challenges. Those studies demonstrate an immune-modulatory role of IL-37 which can be characterized as an important suppressor of innate immunity. We investigated the functions of IL-37 in the CNS and explored the effects of IL-37 on neuronal architecture and function, microglia phenotype, cytokine production and behavior after inflammatory challenge by intraperitoneal LPS-injection. Reduced spine density, activated microglia phenotype and impaired long-term potentiation (LTP) were observed in wild-type mice after LPS injection, whereas hIL-37tg mice showed no impairment. In addition, we crossed the hIL-37tg mouse with an animal model of Alzheimer's disease (APP/PS1) to investigate the anti-inflammatory properties of IL-37 under chronic neuroinflammatory conditions. Our results show that IL-37 is able to limit inflammation in the brain after acute inflammatory events and prevent the loss of cognitive abilities in a mouse model of AD.

scholarly journals Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense Fmr1 mutant mouse model of Fragile X syndrome

2020 ◽  
Author(s):  
Marta Prieto ◽  
Alessandra Folci ◽  
Gwénola Poupon ◽  
Sara Schiavi ◽  
Valeria Buzzelli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Missense Mutations ◽  
Spine Density ◽  
Cgg Repeat ◽  
Electrophysiological Recordings ◽  
Receptor Surface Expression

AbstractFragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. FXS is usually caused by a CGG-repeat expansion in the FMR1 gene leading to its silencing and the loss-of-expression of the Fragile X Mental Retardation Protein (FMRP). Missense mutations were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS in these patients, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that the Fmr1R138Q hippocampus has an increased spine density associated with postsynaptic ultrastructural defects and increased AMPA receptor surface expression. Combining biochemical assays, high-resolution imaging and electrophysiological recordings, we also show that the mutation impairs the hippocampal long-term potentiation (LTP) and leads to socio-cognitive deficits in Fmr1R138Q mice. These findings reveal that the R138Q mutation impacts the synaptic functions of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients.

scholarly journals STEP inhibition prevents Aβ-mediated damage in dendritic complexity and spine density in Alzheimer’s disease.

2020 ◽  
Author(s):  
Manavi Chatterjee ◽  
Jeemin Kwon ◽  
Jessie Benedict ◽  
Marija Kamceva ◽  
Pradeep Kurup ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Mouse Model ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Spine Density ◽  
Protein Tyrosine ◽  
Dendritic Complexity ◽  
Ad Mouse Model

AbstractLoss of dendritic spines and decline of cognitive function are hallmarks of patients with Alzheimer’s disease (AD). Previous studies have shown that AD pathophysiology involves increased expression of a central nervous system-enriched protein tyrosine phosphatase called STEP (STriatal-Enriched protein tyrosine Phosphatase). STEP opposes the development of synaptic strengthening by dephosphorylating substrates, including GluN2B, Pyk2 and ERK1/2. Genetic reduction of STEP as well as pharmacological inhibition of STEP improves cognitive function and hippocampal memory in the 3xTg AD mouse model. Here, we show that the improved cognitive function is accompanied by an increase in synaptic connectivity in cell cultures as well as in the triple transgenic AD mouse model, further highlighting the potential of STEP inhibitors as a therapeutic agent.

scholarly journals Sex-specific divergent maturational trajectories in the post-natal rat basolateral amygdala

2021 ◽  
Author(s):  
Pauline GUILY ◽  
Olivier LASSALLE ◽  
Olivier J MANZONI
Keyword(s):  
Ampa Receptors ◽  
Basolateral Amygdala ◽  
Pyramidal Neurons ◽  
Long Term Potentiation ◽  
Adolescent Females ◽  
Female Rats ◽  
Spine Density ◽  
Cross Sectional ◽  
Stimulus Response ◽  
Male And Female Rats

The basolateral amygdala (BLA), the part of the amygdala complex involved in the transduction of perceptual stimuli into emotion, undergoes profound reorganization at adolescence in rodents and humans. How cellular and synaptic plasticity evolve throughout postnatal development in both sexes is only partially understood. We used a cross-sectional approach to compare the morphology, neuronal, and synaptic properties of BLA neurons in rats of both sexes at adolescence and adulthood. While BLA pyramidal neurons from rats of both sexes displayed similar current-voltage relationships, rheobases, and resting potentials during pubescence, differences in these parameters emerged between sexes at adulthood: BLA neurons were more excitable in males than females. During pubescence, BLA neuron excitability was highest in females and unchanged in males; male action potentials were smaller and shorter than females and fast afterhyperpolarizations were larger in males. During post-natal maturation, no difference in spine density was observed between groups or sexes but spine length increased and decreased in females and males, respectively. A reduction in spine head diameter and volume was observed exclusively in females. Basic synaptic properties also displayed sex-specific maturational differences. Stimulus-response relationships and maximal fEPSP amplitudes where higher in male adolescents compared with adults but were similar in females of both ages. Spontaneous excitatory postsynaptic currents mediated by AMPA receptors were smaller in BLA neurons from adolescent female compared with their adult counterparts but were unchanged in males. These differences did not directly convert into changes in overall synaptic strength estimated from the AMPA/NMDA ratio, which was smaller in adolescent females. Finally, the developmental courses of long-term potentiation and depression (LTP, LTD) were sexually dimorphic. LTP was similarly present during the adolescent period in males and females but was not apparent at adulthood in females. In contrast, LTD followed an opposite development: present in adolescent females and expressed in both sexes at adulthood. These data reveal divergent maturational trajectories in the BLA of male and female rats and suggest cellular substrates to the BLA linked sex-specific behaviors at adolescence and adulthood.

scholarly journals A low repeated dose of Δ9-tetrahydrocannabinol affects memory performance through serotonergic signalling in mice

2021 ◽  
Author(s):  
Lorena Galera-Lopez ◽  
Victoria Salgado-Mendialdua ◽  
Estefania Moreno ◽  
Araceli Bergada-Martinez ◽  
Alex Hoffman ◽  
...  
Keyword(s):  
Memory Impairment ◽  
Low Dose ◽  
Partial Agonist ◽  
Memory Performance ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
High Dose ◽  
Repeated Treatment ◽  
Spine Density ◽  
Cannabinoid Type 1 Receptor

Cannabis is the most widely used illicit drug worldwide. Its principal psychoactive component, ∆9-tetrahydrocannabinol (THC), acts as a partial agonist of the main cannabinoid receptor in the brain, the cannabinoid type-1 receptor (CB1R), being the main responsible for the central effects of THC including memory impairment. CB1Rs may form heterodimers with the serotonin 5-HT2A receptor (5-HT2AR) which were found responsible for the memory impairment produced by acute high dose of THC in mice. In this study we investigated whether a repeated low dose of THC (1 mg/kg), with no acute consequence on memory performance, could eventually have deleterious cognitive effects. We found that such a low dose of THC impairs novel object-recognition memory and fear conditioning memory after repeated treatment (7 days). This deficit was also detected 24 h after the last THC administration. At that time, a general enhancement of c-Fos expression was observed in several brain regions of THC-exposed animals. In addition, THC-treated mice showed a decreased spine density at CA1 pyramidal neurons and reduced long-term potentiation at Schaffer collateral-CA1 synapses. Interestingly, an up-regulation in the expression of CB1R/5-HT2AR heterodimers was observed in the hippocampus of THC-exposed mice and a pre-treatment with the 5-HT2AR antagonist MDL 100,907 (0.01 mg/kg) prevented enhanced heterodimerization and the THC-associated memory impairment. Together, these results reveal the significance of serotonergic signalling through 5-HT2ARs in the memory-impairing effects of repeated low doses of THC.

scholarly journals Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marta Prieto ◽  
Alessandra Folci ◽  
Gwénola Poupon ◽  
Sara Schiavi ◽  
Valeria Buzzelli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Missense Mutations ◽  
Spine Density ◽  
Cgg Repeat ◽  
Electrophysiological Recordings ◽  
Receptor Surface Expression

AbstractFragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS caused by this mutation, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that, in the hippocampus of the Fmr1R138Q mice, neurons show an increased spine density associated with synaptic ultrastructural defects and increased AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, and behavioural testing, we also show that the R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice. These findings reveal the functional impact of the FMRP-R138Q mutation in a mouse model of FXS.

scholarly journals Kalirin-7 is a Key Player in the Formation of Excitatory Synapses in Hippocampal Neurons

2010 ◽  
Vol 10 ◽  
pp. 1655-1666 ◽  
Author(s):  
Xin-Ming Ma
Keyword(s):  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Synapse Formation ◽  
Pdz Domain ◽  
Long Term Potentiation ◽  
Binding Motif ◽  
Excitatory Synapses ◽  
Spine Density ◽  
Chronic Cocaine ◽  
And Function

Kalirin-7 (Kal7), a major isoform of Kalirin in the adult rodent hippocampus, is exclusively localized to the postsynaptic side of mature excitatory synapses in hippocampal neurons. Kal7 interacts with multiple PDZ domain—containing proteins through its unique PDZ binding motif. Overexpression of Kal7 increases spine density and spine size, whereas reduction of endogenous Kal7 expression by small hairpin RNA (shRNA) causes a decrease in synapse number and spine density in cultured hippocampal neurons. Hippocampal CA1 pyramidal neurons of Kal7 knockout (Kal7KO) mice show decreased spine density, spine length, synapse number, and postsynaptic density (PSD) size in their apical dendrites; are deficient in long-term potentiation (LTP); and exhibit decreased frequency of spontaneous excitatory postsynaptic current (sEPSC). Kal7 plays a key role in estrogen-mediated spine/synapse formation in hippocampal neurons. Kal7 is also an essential determinant of dendritic spine formation following chronic cocaine treatment. Kal7 plays a key role in excitatory synapse formation and function.

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