scholarly journals Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP

2021 ◽  
Vol 14 (1) ◽  
pp. 61
Author(s):  
Ernesto Fedele ◽  
Roberta Ricciarelli
Keyword(s):  
Cognitive Deficits ◽  
Long Term Potentiation ◽  
Gold Rush ◽  
New Drugs ◽  
Dose Finding ◽  
Beneficial Effects ◽  
Cyclic Nucleotide Gated Channels ◽  
Term Potentiation ◽  
Cgmp Signaling ◽  
The Central Nervous System

Cyclic guanosine-3′,5′-monophosphate, better known as cyclic-GMP or cGMP, is a classical second messenger involved in a variety of intracellular pathways ultimately controlling different physiological functions. The family of guanylyl cyclases that includes soluble and particulate enzymes, each of which comprises several isoforms with different mechanisms of activation, synthesizes cGMP. cGMP signaling is mainly executed by the activation of protein kinase G and cyclic nucleotide gated channels, whereas it is terminated by its hydrolysis to GMP operated by both specific and dual-substrate phosphodiesterases. In the central nervous system, cGMP has attracted the attention of neuroscientists especially for its key role in the synaptic plasticity phenomenon of long-term potentiation that is instrumental to memory formation and consolidation, thus setting off a “gold rush” for new drugs that could be effective for the treatment of cognitive deficits. In this article, we summarize the state of the art on the neurochemistry of the cGMP system and then review the pre-clinical and clinical evidence on the use of cGMP enhancers in Alzheimer’s disease (AD) therapy. Although preclinical data demonstrates the beneficial effects of cGMP on cognitive deficits in AD animal models, the results of the clinical studies carried out to date are not conclusive. More trials with a dose-finding design on selected AD patient’s cohorts, possibly investigating also combination therapies, are still needed to evaluate the clinical potential of cGMP enhancers.

scholarly journals FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits

2019 ◽  
Vol 28 (22) ◽  
pp. 3777-3791 ◽  
Author(s):  
Wan Yun Ho ◽  
Jer-Cherng Chang ◽  
Sheue-Houy Tyan ◽  
Yi-Chun Yen ◽  
Kenneth Lim ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Long Term Potentiation ◽  
Autism Spectrum ◽  
Dependent Manner ◽  
Spine Density ◽  
Preferential Expression ◽  
Fused In Sarcoma ◽  
Endogenous Expression ◽  
Term Potentiation ◽  
The Central Nervous System

Abstract Pathological fused in sarcoma (FUS) inclusions are found in 10% of patients with frontotemporal dementia and those with amyotrophic lateral sclerosis (ALS) carrying FUS mutations. Current work indicates that FUS mutations may incur gain-of-toxic functions to drive ALS pathogenesis. However, how FUS dysfunction may affect cognition remains elusive. Using a mouse model expressing wild-type human FUS mimicking the endogenous expression pattern and level within the central nervous system, we found that they developed hippocampus-mediated cognitive deficits accompanied by an age-dependent reduction in spine density and long-term potentiation in their hippocampus. However, there were no apparent FUS aggregates, nuclear envelope defects and cytosolic FUS accumulation. These suggest that these proposed pathogenic mechanisms may not be the underlying causes for the observed cognitive deficits. Unbiased transcriptomic analysis identified expression changes in a small set of genes with preferential expression in the neurons and oligodendrocyte lineage cells. Of these, we focused on Sema5a, a gene involved in axon guidance, spine dynamics, Parkinson’s disease and autism spectrum disorders. Critically, FUS binds directly to Sema5a mRNA and regulates Sema5a expression in a FUS-dose-dependent manner. Taken together, our data suggest that FUS-driven Sema5a deregulation may underlie the cognitive deficits in FUS transgenic mice.

Neurotrophins and Proneurotrophins: Focus on Synaptic Activity and Plasticity in the Brain

2017 ◽  
Vol 23 (6) ◽  
pp. 587-604 ◽  
Author(s):  
Julien Gibon ◽  
Philip A. Barker
Keyword(s):  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Cellular Processes ◽  
Term Potentiation ◽  
Neurotrophin 3 ◽  
New Findings ◽  
The Central Nervous System ◽  
The Brain

Neurotrophins have been intensively studied and have multiple roles in the brain. Neurotrophins are first synthetized as proneurotrophins and then cleaved intracellularly and extracellularly. Increasing evidences demonstrate that proneurotrophins and mature neurotrophins exerts opposing role in the central nervous system. In the present review, we explore the role of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) and their respective proform in cellular processes related to learning and memory. We focused on their roles in synaptic activity and plasticity in the brain with an emphasis on long-term potentiation, long-term depression, and basal synaptic transmission in the hippocampus and the temporal lobe area. We also discuss new findings on the role of the Val66Met polymorphism on the BDNF propeptide on synaptic activity.

scholarly journals Modeling Resilience to Damage in Multiple Sclerosis: Plasticity Meets Connectivity

2019 ◽  
Vol 21 (1) ◽  
pp. 143 ◽  
Author(s):  
Mario Stampanoni Bassi ◽  
Ennio Iezzi ◽  
Luigi Pavone ◽  
Georgia Mandolesi ◽  
Alessandra Musella ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Synaptic Plasticity ◽  
Network Architecture ◽  
White Matter Lesions ◽  
Long Term Potentiation ◽  
Chronic Inflammatory Disease ◽  
Brain Network ◽  
Term Potentiation ◽  
The Central Nervous System ◽  
Efficient Information

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelinating white matter lesions and neurodegeneration, with a variable clinical course. Brain network architecture provides efficient information processing and resilience to damage. The peculiar organization characterized by a low number of highly connected nodes (hubs) confers high resistance to random damage. Anti-homeostatic synaptic plasticity, in particular long-term potentiation (LTP), represents one of the main physiological mechanisms underlying clinical recovery after brain damage. Different types of synaptic plasticity, including both anti-homeostatic and homeostatic mechanisms (synaptic scaling), contribute to shape brain networks. In MS, altered synaptic functioning induced by inflammatory mediators may represent a further cause of brain network collapse in addition to demyelination and grey matter atrophy. We propose that impaired LTP expression and pathologically enhanced upscaling may contribute to disrupting brain network topology in MS, weakening resilience to damage and negatively influencing the disease course.

Neuronal calcium sensors and synaptic plasticity

2009 ◽  
Vol 37 (6) ◽  
pp. 1359-1363 ◽  
Author(s):  
Mascia Amici ◽  
Andrew Doherty ◽  
Jihoon Jo ◽  
David Jane ◽  
Kwangwook Cho ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Signalling Pathways ◽  
Calcium Sensor ◽  
Calcium Sensors ◽  
Term Potentiation ◽  
Neuronal Calcium Sensor Protein ◽  
The Central Nervous System ◽  
Sensor Proteins

Calcium entry plays a major role in the induction of several forms of synaptic plasticity in different areas of the central nervous system. The spatiotemporal aspects of these calcium signals can determine the type of synaptic plasticity induced, e.g. LTP (long-term potentiation) or LTD (long-term depression). A vast amount of research has been conducted to identify the molecular and cellular signalling pathways underlying LTP and LTD, but many components remain to be identified. Calcium sensor proteins are thought to play an essential role in regulating the initial part of synaptic plasticity signalling pathways. However, there is still a significant gap in knowledge, and it is only recently that evidence for the importance of members of the NCS (neuronal calcium sensor) protein family has started to emerge. The present minireview aims to bring together evidence supporting a role for NCS proteins in plasticity, focusing on emerging roles of NCS-1 and hippocalcin.

Klk8, a multifunctional protease in the brain and skin: analysis of knockout mice

2010 ◽  
Vol 391 (4) ◽  
Author(s):  
Shigetaka Yoshida
Keyword(s):  
Central Nervous System ◽  
Long Term Potentiation ◽  
Term Potentiation ◽  
The Central Nervous System ◽  
Synaptic Changes ◽  
Adhesive Molecules ◽  
High Level ◽  
Activity Dependent ◽  
The Brain

Abstract Klk8 is a tryptic serine protease with limited substrate specificity. Klk8 mRNA is expressed in many developing organs, whereas its expression is confined to limited regions, including the hippocampus, in adults. In the hippocampus, Klk8 is involved in activity-dependent synaptic changes such as long-term potentiation, which was found to be suppressed in Klk8 knockout (KO) mice. Oligodendrocytes only expressed Klk8 mRNA after injury to the central nervous system. The epidermis of the skin is one of the tissues that exhibits a high level of KLK8 expression. Klk8 might be involved in desquamation through the degradation of adhesive molecules that connect layers of the epidermis. Klk8 might thus be involved in tissue development and rearrangement.

scholarly journals Oligodendrocytic Na+-K+-Cl– co-transporter 1 activity facilitates axonal conduction and restores plasticity in the adult mouse brain

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yoshihiko Yamazaki ◽  
Yoshifumi Abe ◽  
Satoshi Fujii ◽  
Kenji F. Tanaka
Keyword(s):  
Mouse Brain ◽  
Adult Mouse ◽  
Long Term Potentiation ◽  
Adaptive Plasticity ◽  
Adult Mouse Brain ◽  
Adult Mice ◽  
Term Potentiation ◽  
The Central Nervous System ◽  
Juvenile Mouse

AbstractThe juvenile brain presents plasticity. Oligodendrocytes are the myelinating cells of the central nervous system and myelination can be adaptive. Plasticity decreases from juvenile to adulthood. The mechanisms involving oligodendrocytes underlying plasticity are unclear. Here, we show Na+-K+-Cl– co-transporter 1 (NKCC1), highly expressed in the juvenile mouse brain, regulates the oligodendrocyte activity from juvenile to adulthood in mice, as shown by optogenetic manipulation of oligodendrocytes. The reduced neuronal activity in adults was restored by Nkcc1 overexpression in oligodendrocytes. Moreover, in adult mice overexpressing Nkcc1, long-term potentiation and learning were facilitated compared to age-matched controls. These findings demonstrate that NKCC1 plays a regulatory role in the age-dependent activity of oligodendrocytes, furthermore inducing activation of NKCC1 in oligodendrocytes can restore neuronal plasticity in the adult mouse brain.

scholarly journals Simvastatin Impairs Hippocampal Synaptic Plasticity and Cognitive Function in Mice

2021 ◽  
Author(s):  
Yujun Guo ◽  
Guichang Zou ◽  
Keke Qi ◽  
Jin Jin ◽  
Lei Yao ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Memory Function ◽  
Long Term Potentiation ◽  
Drug Discontinuation ◽  
Cholesterol Levels ◽  
Hippocampal Synaptic Plasticity ◽  
Term Potentiation ◽  
The Central Nervous System

Abstract Lipophilic statins which are blood brain barrier (BBB) permeable are speculated to affect the cholesterol synthesis and neural functions in the central nervous system. However, whether these statins can affect cholesterol levels and synaptic plasticity in hippocampus and the in vivo consequence remain unclear. Here, we report that long-term subcutaneous treatments of simvastatin significantly impair mouse hippocampal synaptic plasticity, reflected by the attenuated long-term potentiation of field excitatory postsynaptic potentials. The simvastatin administration causes a deficiency in recognition and spatial memory but fails to affect motor ability and anxiety behaviors in the mice. Mass spectrometry imaging indicates a significant decrease in cholesterol intensity in hippocampus of the mice receiving chronic simvastatin treatments. Such effects of simvastatin are transient because drug discontinuation can restore the hippocampal cholesterol level and synaptic plasticity and the memory function. These findings may provide further clues to elucidate the mechanisms of neurological side effects, especially the brain cognitive

scholarly journals A centronuclear myopathy-causing mutation in dynamin-2 perturbs the actin-dependent structure of dendritic spines leading to excitatory synaptic defects in a murine model of the disease

2021 ◽  
Author(s):  
JORGE ARRIAGADA-DIAZ ◽  
Barbara Gomez ◽  
Lorena Prado-Vega ◽  
MICHELLE MATTAR-ARAOS ◽  
MARJORIE LABRANA-ALLENDE ◽  
...  
Keyword(s):  
Nervous System ◽  
Long Term Potentiation ◽  
Neuromuscular Disorder ◽  
Centronuclear Myopathy ◽  
Term Potentiation ◽  
The Central Nervous System ◽  
Central Synapses ◽  
Cytoskeleton Dynamics ◽  
Dynamin 2 ◽  
Cognitive Defects

Dynamin-2 is a large GTP-ase, member of the dynamin superfamily, that regulates membrane remodeling and cytoskeleton dynamics. In the mammalian nervous system dynamin-2 modulates synaptic vesicle (SV)-recycling at the nerve terminals and receptor-trafficking to and from postsynaptic densities (PSDs). Mutations in dynamin-2 cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterized by progressive weakness and atrophy of distal skeletal muscles. Cognitive defects have also been reported in dynamin-2-linked CNM patients suggesting a concomitant impairment of the central nervous system. Here we addressed the mechanisms that lead to cognitive defects in dynamin-2-linked CNM using a knock-in mouse model that harbors the p.R465W mutation in dynamin-2, the most common causing CNM. Our results show that these mice exhibit reduced capability to learn and acquire spatial and recognition memory, impaired long-term potentiation of the excitatory synaptic strength and perturbed dendritic spine morphology, which seem to be associated with actin defects. Together, these data reveal for the first time that structural and functional synaptic defects underlie cognitive defects in the CNM context. In addition our results contribute to the still scarce knowledge about the importance of dynamin-2 at central synapses.

Sign in / Sign up

Export Citation Format

Share Document