scholarly journals Preservation of dendritic spine morphology and postsynaptic signaling markers after treatment with solid lipid curcumin particles in the 5xFAD mouse model of Alzheimer’s disease

2020 ◽  
Author(s):  
Panchanan Maiti ◽  
Zackary L Bowers ◽  
Ali Bourcier ◽  
Jarod MOrse ◽  
Gary L Dunbar
Keyword(s):  
Alzheimer’S Disease ◽  
Cognitive Function ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Amyloid Plaque ◽  
Spine Density ◽  
Solid Lipid ◽  
Dendritic Spine Density ◽  
Synaptic Markers ◽  
5Xfad Mice

Abstract Background Synaptic failure is one of the principal events associated with cognitive dysfunction in Alzheimer’s disease (AD). Preservation of existing synapses and prevention of synaptic loss are promising strategies to preserve cognitive function in AD patients. As a potent natural anti-oxidant, anti-amyloid, anti-inflammatory polyphenol, curcumin (Cur) shows great promise as a therapy for AD. However, hydrophobicity of natural Cur limits its solubility, stability, bioavailability and clinical utility for AD therapy. We have demonstrated that solid lipid curcumin particles (SLCP) have greater therapeutic potential than natural Cur in vitro and in vivo models of AD. In the present study, we have investigated whether SLCP has any preservative role on affected dendritic spines and synaptic markers in 5xFAD mice.Methods Six- and 12-month-old 5xFAD and age-matched wild-type mice received oral administration of SLCP (100 mg/kg body weight) or equivalent amounts of vehicle for 2 months. Neuronal morphology, neurodegeneration and amyloid plaque load were investigated from prefrontal cortex (PFC), entorhinal cortex (EC), CA1, CA3 and the subicular complex (SC). Further, dendritic spine density of apical and basal branches were studied by Golgi-Cox stain. Further, synaptic markers, such as synaptophysin, PSD95, Shank, Homer, Drebrin, kalirin-7, CREB and phosphorylated CREB (pCREB) were studied using Western blots. Finally, cognitive and motor functions were assessed using open field, novel object recognition (NOR) and Morris water maze (MWM) tasks after treatment with SLCP.Results We observed an increase number of pyknotic and degenerated cells in all these brain areas in 5xFAD mice and SLCP treatment partially protected against those losses. Decrease in dendritic arborization and dendritic spine density from primary and secondary apical and basal branches were observed in PFC, EC, CA1, CA3 in both 6- and 12-month-old 5xFAD mice and SLCP treatments partially preserved the normal morphology of these dendritic spines. In addition, pre- and post-synaptic protein markers were also restored by SLCP treatment. Furthermore, SLCP treatment improved NOR and cognitive function in 5xFAD mice.Conclusions Overall, these findings indicate that use of SLCP exerts neuroprotective properties by decreasing amyloid plaque burden, preventing neuronal death, as well as preservation of dendritic spine density and synaptic markers in the 5xFAD mice.

scholarly journals Preservation of dendritic spine morphology and postsynaptic signaling markers after treatment with solid lipid curcumin particles in the 5xFAD mouse model of Alzheimer’s amyloidosis

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Panchanan Maiti ◽  
Zackary Bowers ◽  
Ali Bourcier-Schultz ◽  
Jarod Morse ◽  
Gary L. Dunbar
Keyword(s):  
Cognitive Function ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Amyloid Plaque ◽  
Spine Density ◽  
In Vivo Models ◽  
Solid Lipid ◽  
Dendritic Spine Density ◽  
Synaptic Markers ◽  
5Xfad Mice

Abstract Background Synaptic failure is one of the principal events associated with cognitive dysfunction in Alzheimer’s disease (AD). Preservation of existing synapses and prevention of synaptic loss are promising strategies to preserve cognitive function in AD patients. As a potent natural anti-oxidant, anti-amyloid, and anti-inflammatory polyphenol, curcumin (Cur) shows great promise as a therapy for AD. However, hydrophobicity of natural Cur limits its solubility, stability, bioavailability, and clinical utility for AD therapy. We have demonstrated that solid lipid curcumin particles (SLCP) have greater therapeutic potential than natural Cur in vitro and in vivo models of AD. In the present study, we have investigated whether SLCP has any preservative role on affected dendritic spines and synaptic markers in 5xFAD mice. Methods Six- and 12-month-old 5xFAD and age-matched wild-type mice received oral administration of SLCP (100 mg/kg body weight) or equivalent amounts of vehicle for 2 months. Neuronal morphology, neurodegeneration, and amyloid plaque load were investigated from prefrontal cortex (PFC), entorhinal cortex (EC), CA1, CA3, and the subicular complex (SC). In addition, the dendritic spine density from apical and basal branches was studied by Golgi-Cox stain. Further, synaptic markers, such as synaptophysin, PSD95, Shank, Homer, Drebrin, Kalirin-7, CREB, and phosphorylated CREB (pCREB) were studied using Western blots. Finally, cognitive and motor functions were assessed using open-field, novel object recognition (NOR) and Morris water maze (MWM) tasks after treatment with SLCP. Results We observed an increased number of pyknotic and degenerated cells in all these brain areas in 5xFAD mice and SLCP treatment partially protected against those losses. Decrease in dendritic arborization and dendritic spine density from primary, secondary, and tertiary apical and basal branches were observed in PFC, EC, CA1, and CA3 in both 6- and 12-month-old 5xFAD mice, and SLCP treatments partially preserved the normal morphology of these dendritic spines. In addition, pre- and postsynaptic protein markers were also restored by SLCP treatment. Furthermore, SLCP treatment improved NOR and cognitive function in 5xFAD mice. Conclusions Overall, these findings indicate that use of SLCP exerts neuroprotective properties by decreasing amyloid plaque burden, preventing neuronal death, and preserving dendritic spine density and synaptic markers in the 5xFAD mice.

scholarly journals RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer’s disease

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Leticia Pérez-Sisqués ◽  
Anna Sancho-Balsells ◽  
Júlia Solana-Balaguer ◽  
Genís Campoy-Campos ◽  
Marcel Vives-Isern ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Mrna Levels ◽  
Spine Density ◽  
Memory Impairments ◽  
Protein Levels ◽  
Synaptic Markers ◽  
5Xfad Mice

AbstractRTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death. Its downregulation in Parkinson’s and Huntington’s disease models ameliorates the pathological phenotypes. In the context of Alzheimer’s disease (AD), the coding gene for RTP801, DDIT4, is responsive to Aβ and modulates its cytotoxicity in vitro. Also, RTP801 mRNA levels are increased in AD patients’ lymphocytes. However, the involvement of RTP801 in the pathophysiology of AD has not been yet tested. Here, we demonstrate that RTP801 levels are increased in postmortem hippocampal samples from AD patients. Interestingly, RTP801 protein levels correlated with both Braak and Thal stages of the disease and with GFAP expression. RTP801 levels are also upregulated in hippocampal synaptosomal fractions obtained from murine 5xFAD and rTg4510 mice models of the disease. A local RTP801 knockdown in the 5xFAD hippocampal neurons with shRNA-containing AAV particles ameliorates cognitive deficits in 7-month-old animals. Upon RTP801 silencing in the 5xFAD mice, no major changes were detected in hippocampal synaptic markers or spine density. Importantly, we found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD.

scholarly journals Bergmann glial ensheathment of dendritic spines regulates synapse number without affecting spine motility

2010 ◽  
Vol 6 (3) ◽  
pp. 193-200 ◽  
Author(s):  
Jocelyn J. Lippman Bell ◽  
Tamar Lordkipanidze ◽  
Natalie Cobb ◽  
Anna Dunaevsky
Keyword(s):  
Purkinje Cell ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Adenoviral Vector ◽  
Spine Density ◽  
Dendritic Spine Density ◽  
Spine Dynamics

In the cerebellum, lamellar Bergmann glial (BG) appendages wrap tightly around almost every Purkinje cell dendritic spine. The function of this glial ensheathment of spines is not entirely understood. The development of ensheathment begins near the onset of synaptogenesis, when motility of both BG processes and dendritic spines are high. By the end of the synaptogenic period, ensheathment is complete and motility of the BG processes decreases, correlating with the decreased motility of dendritic spines. We therefore have hypothesized that ensheathment is intimately involved in capping synaptogenesis, possibly by stabilizing synapses. To test this hypothesis, we misexpressed GluR2 in an adenoviral vector in BG towards the end of the synaptogenic period, rendering the BG α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) Ca2+-impermeable and causing glial sheath retraction. We then measured the resulting spine motility, spine density and synapse number. Although we found that decreasing ensheathment at this time does not alter spine motility, we did find a significant increase in both synaptic pucta and dendritic spine density. These results indicate that consistent spine coverage by BG in the cerebellum is not necessary for stabilization of spine dynamics, but is very important in the regulation of synapse number.

scholarly journals Hippocampal CA1 Pyramidal Neurons ofMecp2Mutant Mice Show a Dendritic Spine Phenotype Only in the Presymptomatic Stage

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Christopher A. Chapleau ◽  
Elena Maria Boggio ◽  
Gaston Calfa ◽  
Alan K. Percy ◽  
Maurizio Giustetto ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Pyramidal Neurons ◽  
Mutant Mice ◽  
Spine Density ◽  
Ca1 Pyramidal Neurons ◽  
Dendritic Spine Density ◽  
Presymptomatic Stage ◽  
Deficient Mice

Alterations in dendritic spines have been documented in numerous neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, an X chromosome-linked disorder associated with mutations inMECP2, is the leading cause of intellectual disabilities in women. Neurons inMecp2-deficient mice show lower dendritic spine density in several brain regions. To better understand the role of MeCP2 on excitatory spine synapses, we analyzed dendritic spines of CA1 pyramidal neurons in the hippocampus ofMecp2tm1.1Jaemale mutant mice by either confocal microscopy or electron microscopy (EM). At postnatal-day 7 (P7), well before the onset of RTT-like symptoms, CA1 pyramidal neurons from mutant mice showed lower dendritic spine density than those from wildtype littermates. On the other hand, at P15 or later showing characteristic RTT-like symptoms, dendritic spine density did not differ between mutant and wildtype neurons. Consistently, stereological analyses at the EM level revealed similar densities of asymmetric spine synapses in CA1stratum radiatumof symptomatic mutant and wildtype littermates. These results raise caution regarding the use of dendritic spine density in hippocampal neurons as a phenotypic endpoint for the evaluation of therapeutic interventions in symptomaticMecp2-deficient mice. However, they underscore the potential role of MeCP2 in the maintenance of excitatory spine synapses.

scholarly journals Sex differences in dendritic spine density and morphology in auditory and visual cortices in adolescence and adulthood

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Emily M. Parker ◽  
Nathan L. Kindja ◽  
Claire E. J. Cheetham ◽  
Robert A. Sweet
Keyword(s):  
Sex Differences ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Brain Regions ◽  
Spine Density ◽  
Female Mice ◽  
Dendritic Spine Density ◽  
Layer 4 ◽  
Visual Cortices ◽  
Mushroom Spines

AbstractDendritic spines are small protrusions on dendrites that endow neurons with the ability to receive and transform synaptic input. Dendritic spine number and morphology are altered as a consequence of synaptic plasticity and circuit refinement during adolescence. Dendritic spine density (DSD) is significantly different based on sex in subcortical brain regions associated with the generation of sex-specific behaviors. It is largely unknown if sex differences in DSD exist in auditory and visual brain regions and if there are sex-specific changes in DSD in these regions that occur during adolescent development. We analyzed dendritic spines in 4-week-old (P28) and 12-week-old (P84) male and female mice and found that DSD is lower in female mice due in part to fewer short stubby, long stubby and short mushroom spines. We found striking layer-specific patterns including a significant age by layer interaction and significantly decreased DSD in layer 4 from P28 to P84. Together these data support the possibility of developmental sex differences in DSD in visual and auditory regions and provide evidence of layer-specific refinement of DSD over adolescent brain development.

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