Deficits in N-Methyl-D-Aspartate Receptor Function and Synaptic Plasticity in Hippocampal CA1 in APP/PS1 Mouse Model of Alzheimer’s Disease

The N-methyl-D-aspartate receptor is a critical molecule for synaptic plasticity and cognitive function. Impaired synaptic plasticity is thought to contribute to the cognitive impairment associated with Alzheimer’s disease (AD). However, the neuropathophysiological alterations of N-methyl-D-aspartate receptor (NMDAR) function and synaptic plasticity in hippocampal CA1 in transgenic rodent models of AD are still unclear. In the present study, APP/PS1 mice were utilized as a transgenic model of AD, which exhibited progressive cognitive impairment including defective working memory, recognition memory, and spatial memory starting at 6 months of age and more severe by 8 months of age. We found an impaired long-term potentiation (LTP) and reduced NMDAR-mediated spontaneous excitatory postsynaptic currents (sEPSCs) in the hippocampal CA1 of APP/PS1 mice with 8 months of age. Golgi staining revealed that dendrites of pyramidal neurons had shorter length, fewer intersections, and lower spine density in APP/PS1 mice compared to control mice. Further, the reduced expression levels of NMDAR subunits, PSD95 and SNAP25 were observed in the hippocampus of APP/PS1 mice. These results suggest that NMDAR dysfunction, impaired synaptic plasticity, and disrupted neuronal morphology constitute an important part of the neuropathophysiological alterations associated with cognitive impairment in APP/PS1 mice.

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Enduring glucocorticoid-evoked exacerbation of synaptic plasticity disruption in male rats modelling early Alzheimer’s disease amyloidosis

Neuropsychopharmacology ◽

10.1038/s41386-021-01056-9 ◽

2021 ◽

Author(s):

Yingjie Qi ◽

Igor Klyubin ◽

Tomas Ondrejcak ◽

Neng-Wei Hu ◽

Michael J. Rowan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Transgenic Animals ◽

Long Term Potentiation ◽

Male Rats ◽

Model Of Alzheimer’S Disease ◽

Term Potentiation ◽

Early Alzheimer’S Disease

AbstractSynaptic dysfunction is a likely proximate cause of subtle cognitive impairment in early Alzheimer’s disease. Soluble oligomers are the most synaptotoxic forms of amyloid ß-protein (Aß) and mediate synaptic plasticity disruption in Alzheimer’s disease amyloidosis. Because the presence and extent of cortisol excess in prodromal Alzheimer’s disease predicts the onset of cognitive symptoms we hypothesised that corticosteroids would exacerbate the inhibition of hippocampal synaptic long-term potentiation in a rat model of Alzheimer’s disease amyloidosis. In a longitudinal experimental design using freely behaving pre-plaque McGill-R-Thy1-APP male rats, three injections of corticosterone or the glucocorticoid methylprednisolone profoundly disrupted long-term potentiation induced by strong conditioning stimulation for at least 2 months. The same treatments had a transient or no detectible detrimental effect on synaptic plasticity in wild-type littermates. Moreover, corticosterone-mediated cognitive dysfunction, as assessed in a novel object recognition test, was more persistent in the transgenic animals. Evidence for the involvement of pro-inflammatory mechanisms was provided by the ability of the selective the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome inhibitor Mcc950 to reverse the synaptic plasticity deficit in corticosterone-treated transgenic animals. The marked prolongation of the synaptic plasticity disrupting effects of brief corticosteroid excess substantiates a causal role for hypothalamic-pituitary-adrenal axis dysregulation in early Alzheimer’s disease.

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Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.722580 ◽

2021 ◽

Vol 13 ◽

Author(s):

Yongchuan Shi ◽

Jinpeng Lv ◽

Ling Chen ◽

Guojun Luo ◽

Mengjia Tao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Prefrontal Cortex ◽

Mouse Model ◽

Long Term Potentiation ◽

Synaptic Proteins ◽

Novel Object ◽

Model Of Alzheimer’S Disease ◽

Synaptic Failure

Phosphodiesterase 4 (PDE4)-dependent cAMP signaling plays a crucial role in cognitive impairment associated with Alzheimer’s disease (AD). However, whether inhibition of PDE4 subtypes or their splice variants in the prefrontal cortex positively regulates synaptic plasticity and antioxidative stress, and reverses β-amyloid 1–42 (Aβ1–42, Aβ42)-induced cognitive impairment still need to be clarified. The present study determined whether and how PDE4D knockdown by microinjection of lenti-PDE4D-miRNA into the prefrontal cortex reversed Aβ1–42-induced cognitive impairment in behavioral, neurochemical, and molecular biology assays. The results suggested that PDE4D knockdown increased time to explore the novel object and decreased latency to leave the platform in novel object recognition and step-down passive avoidance tests. Further study suggested that PDE4D knockdown decreased the number of working memory errors in the eight-arm maze test. These effects were prevented by PKA inhibitor H89. The subsequent experiment suggested that inhibition of PDE4D in the prefrontal cortex rescued the long-term potentiation (LTP) and synaptic proteins’ expression; it also increased antioxidant response by increasing superoxide dismutase (SOD) and decreasing malondialdehyde (MDA) levels. PDE4D knockdown also increased phosphorylated cAMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BNDF), and anti-apoptotic proteins’ expression, i.e., the ratio of Bcl-2/Bax, and decreased caspase-3 level in the prefrontal cortex. These findings extend the previous findings and support the hypothesis that RNA interference-mediated PDE4D knockdown in the prefrontal cortex ameliorated memory loss associated with synaptic failure in an AD mouse model by its antioxidant, anti-apoptotic, and neuroprotective properties.

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Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer’s disease

Clinical Epigenetics ◽

10.1186/s13148-015-0142-9 ◽

2015 ◽

Vol 7 (1) ◽

Cited By ~ 31

Author(s):

M. Cuadrado-Tejedor ◽

C. Garcia-Barroso ◽

J. Sanzhez-Arias ◽

S. Mederos ◽

O. Rabal ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Synaptic Plasticity ◽

Mouse Model ◽

Histone Deacetylase ◽

Model Of Alzheimer’S Disease ◽

Phosphodiesterase 5

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A GLP-1/GIP Dual Receptor Agonist DA4-JC Effectively Attenuates Cognitive Impairment and Pathology in the APP/PS1/Tau Model of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210256 ◽

2021 ◽

pp. 1-20

Author(s):

Hong-Yan Cai ◽

Dan Yang ◽

Jing Qiao ◽

Jun-Ting Yang ◽

Zhao-Jun Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Receptor Agonist ◽

Close Correlation ◽

Long Term Potentiation ◽

Golgi Method ◽

Protective Effects ◽

Model Of Alzheimer’S Disease

Background: Alzheimer’s disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. Objective: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. Methods: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers. Results: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. Conclusion: DA4-JC is a promising drug for the treatment of AD.

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Dysregulation of Astrocyte–Neuronal Communication in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22157887 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7887

Author(s):

Carmen Nanclares ◽

Andres Mateo Baraibar ◽

Alfonso Araque ◽

Paulo Kofuji

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Synaptic Plasticity ◽

Neuronal Excitability ◽

Active Role ◽

Ionic Homeostasis ◽

Neuronal Communication ◽

Structural Support

Recent studies implicate astrocytes in Alzheimer’s disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain also indicates their role in regulating synaptic plasticity and neuronal excitability via the release of neuroactive substances named gliotransmitters. Here, we review how this “active” role of astrocytes at synapses could contribute to synaptic and neuronal network dysfunction and cognitive impairment in AD.

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

Scientific Reports ◽

10.1038/s41598-021-94992-x ◽

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.

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Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction

Journal of Alzheimer s Disease ◽

10.3233/jad-201599 ◽

2021 ◽

pp. 1-16

Author(s):

Wei Wei ◽

Yinghua Liu ◽

Chunling Dai ◽

Narjes Baazaoui ◽

Yunn-Chyn Tung ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Synaptic Plasticity ◽

Cognitive Function ◽

Early Development ◽

Neurodegenerative Disorder ◽

Synaptic Dysfunction ◽

Early Postnatal Development ◽

Wild Type Female

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction. Objective: To explore strategies for early intervention to prevent Alzheimer’s disease. Methods: In the present study, we investigated the effect of treatment during early development with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLAG-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated. Results: P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice. Conclusion: These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies.

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Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201367 ◽

2021 ◽

pp. 1-20

Author(s):

Daniel Cuervo-Zanatta ◽

Jaime Garcia-Mena ◽

Claudia Perez-Cruz

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Gut Microbiota ◽

Cognitive Skills ◽

Amyloid Β ◽

Short Chain Fatty Acids ◽

Mice Model ◽

Model Of Alzheimer’S Disease ◽

Cognitive Deficiencies

Background: Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer’s disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice. Objective: The aim of this work was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design. Methods: Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences. Results: We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice. Conclusion: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD.

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