Combination Therapy of Donepezil and Environmental Enrichment on Memory Deficits in Amyloid-Beta-Induced Alzheimer's Disease Rats

2021 ◽  
Author(s):  
Jamileh Gholami ◽  
Sajad Sahab Negah ◽  
Arezoo Rajabian ◽  
Vahid Hajali
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Combination Therapy ◽  
Spatial Memory ◽  
Amyloid Beta ◽  
Environmental Enrichment ◽  
Acetylcholinesterase Inhibitor ◽  
Cognitive Stimulation ◽  
Spatial Learning And Memory ◽  
Bdnf Expression

Abstract Alzheimer's disease (AD) is progressive neurodegeneration known as the most common cause of dementia, and it is the sixth leading cause of death in older people. Given the promising data on the additive effect of combination therapy with donepezil (Aricept), an acetylcholinesterase inhibitor (AChEI), and regarding the similar neuronal mechanisms through them donepezil and environmental enrichment (EE) exert their enhancing effects on cognition; we asked whether simultaneous treatment with two paradigms in amyloid-beta-induced AD rats may lead to greater cognitive improvements than either treatment individually. AD was induced by intrahippocampal injection of amyloid-beta (1-42, 6 µg), and donepezil was orally administrated (4 mg/kg) for 21 days. Environmental enrichment consisted of housing animals in large cages (50× 50× 50 cm) containing a running wheel and differently shaped objects for 21 days. Spatial learning and memory were assessed in the Morris water maze (MWM) and Real-time PCR was performed to assess the expression of brain-derived neurotrophic factor (BDNF) and M1 muscarinic acetylcholine receptor (AchM1R) within the hippocampus. Spatial memory was impaired in AD animals, and while neither pretreatment with donepezil nor EE alone could significantly restore spatial memory scores in AD rats, combination therapy was effective. BDNF expression was suppressed in AD rats and pretreatment with donepezil plus EE could increase it to the saline levels. The data suggest that a cholinesterase inhibitor and cognitive stimulation can be used effectively in combination to improve cognitive loss in an AD rat model.

scholarly journals The Beneficial Effects of Physical Running on Dendritic Spines and Amyloid-Beta Pathology in 3xTg-AD Mice

2021 ◽  
Author(s):  
Benke Xu ◽  
Yun He ◽  
Lian Liu ◽  
Guosheng Ye ◽  
Lulu Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Spatial Memory ◽  
Amyloid Beta ◽  
Dendritic Spines ◽  
Wheel Running ◽  
Synaptic Proteins ◽  
Aβ Peptides ◽  
People With Dementia

Abstract Background: Memory loss is the key symptom of Alzheimer's disease (AD). As successful drug treatments have not yet been identified, non-pharmaceutical intervention, such as physical exercise has been recognized as an effective strategy to improve memory function of people with dementia. Here we investigated the effect of prolonged physical running on hippocampal-dependent spatial memory and underlying mechanisms in 3xTg-AD mouse, a well-established rodent model of Alzheimer's disease (AD).Methods: 3xTg-AD transgenic mice that bear three mutations of AD were used and compared with non-transgenic mice. Voluntary wheel running continued for 5 months (1 hour per day, 5 days per week), followed by spatial memory testing. At the end of behavior testing, dendritic spines, synapses, and synaptic proteins as well as amyloid-beta (Aβ) pathology were analyzed in dorsal hippocampus. Results: Running improved hippocampal-dependent spatial memory in 3xTg-AD mice. This running strategy prevented both thin and mushroom-type spines on CA1 pyramidal cells in 3xTg-AD mice, whereas the effects of running in non-transgenic mice were limited to thin spines. The enormous effects of running on spines were accompanied by increased synapses and higher expressions of synaptic proteins. Notably, running downregulated the processing of amyloid precursor protein, resulting in reduced Aβ peptides, and spatial memory performance correlated with levels of Aβ peptides including Aβ1-40 and Aβ1-42. Conclusion: These data suggest that prolonged running may improve memory in preclinical AD via slowing down amyloid pathology and preventing loss of synaptic contacts.

Enhancing Therapeutic Efficacy of Donepezil by Combined Therapy; A Comprehensive Review

2020 ◽  
Vol 26 ◽  
Author(s):  
Xi Rong ◽  
Liwei Jiang ◽  
Meijie Qu ◽  
Syed Shams ul Hassan ◽  
Zongchao Liu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Combination Therapy ◽  
Dominant Role ◽  
Combined Therapy ◽  
Acetylcholinesterase Inhibitor ◽  
Symptomatic Relief ◽  
Current Status ◽  
Disease Modifying Agents

: Combination therapy involving different therapeutic strategies mostly provides more rapid and effective results as compared to monotherapy in diverse areas of clinical practice. The most worldwide famous acetylcholinesterase inhibitor (AChEIs) donepezil for its dominant role in Alzheimer’s disease (AD) has also attracted the eyes of many pharmaceuticals regarding its promising pharmacological potencies such as neuroprotective, muscle relaxant, and sleep. Recently a combination of donepezil with other agents has displayed better desirable results in the management of several disorders, including most common Alzheimer’s disease (AD). This study encircles all the data regarding the therapeutic effect of donepezil in its combination with other agents and explains its therapeutic targets, mode of action. Furthermore, this review also puts light on the current status of donepezil with other agents in clinical trials. The combo therapy of donepezil with symptomatic relief drugs and disease-modifying agents opens a new road for the treatment of multiple pathological disorders. To best known to our knowledge, this is the first report encircling all the pharmacologic effects of donepezil in its combination therapy with other agents and their current status in clinical trials.

scholarly journals Environmental Enrichment Effects on the Brain-Derived Neurotrophic Factor Expression in Healthy Condition, Alzheimer’s Disease, and Other Neurodegenerative Disorders

2021 ◽  
pp. 1-18
Author(s):  
Debora Cutuli ◽  
Eugenia Landolfo ◽  
Laura Petrosini ◽  
Francesca Gelfo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurotrophic Factor ◽  
Environmental Enrichment ◽  
Brain Plasticity ◽  
Regulation Of Gene Expression ◽  
Experimental Studies ◽  
Brain Derived Neurotrophic Factor ◽  
Bdnf Expression ◽  
The Brain

Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophin family, is known to be heavily involved in synaptic plasticity processes that support brain development, post-lesion regeneration, and cognitive performances, such as learning and memory. Evidence indicates that BDNF expression can be epigenetically regulated by environmental stimuli and thus can mediate the experience-dependent brain plasticity. Environmental enrichment (EE), an experimental paradigm based on the exposure to complex stimulations, constitutes an efficient means to investigate the effects of high-level experience on behavior, cognitive processes, and neurobiological correlates, as the BDNF expression. In fact, BDNF exerts a key role in mediating and promoting EE-induced plastic changes and functional improvements in healthy and pathological conditions. This review is specifically aimed at providing an updated framework of the available evidence on the EE effects on brain and serum BDNF levels, by taking into account both changes in protein expression and regulation of gene expression. A further purpose of the present review is analyzing the potential of BDNF regulation in coping with neurodegenerative processes characterizing Alzheimer’s disease (AD), given BDNF expression alterations are described in AD patients. Moreover, attention is also paid to EE effects on BDNF expression in other neurodegenerative disease. To investigate such a topic, evidence provided by experimental studies is considered. A deeper understanding of environmental ability in modulating BDNF expression in the brain may be fundamental in designing more tuned and effective applications of complex environmental stimulations as managing approaches to AD.

scholarly journals Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model

2018 ◽  
Vol 115 (47) ◽  
pp. E11148-E11157 ◽  
Author(s):  
Karolina J. Janczura ◽  
Claude-Henry Volmar ◽  
Gregory C. Sartor ◽  
Sunil J. Rao ◽  
Natalie R. Ricciardi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Tau Phosphorylation ◽  
Spatial Learning And Memory ◽  
Bdnf Expression ◽  
Age Related ◽  
Swedish Mutation ◽  
Ad Mouse Model ◽  
Tau Acetylation

Alzheimer’s disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of β-amyloid (Aβ) plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-associated sites, reduces β-secretase cleavage of the amyloid precursor protein (APP), and decreases Aβ1–42 accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathological tau phosphorylation at Thr181, Ser202, and Ser396, increases levels of the Aβ degrading enzyme Neprilysin in plasma, decreases Aβ1–42 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Aβ1–42 accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOEε4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology, supporting the notion that HDAC3 may be a disease-modifying therapeutic target.

scholarly journals The Effects of Physical Running on Dendritic Spines and Amyloid-Beta Pathology in 3xTg-AD Male Mice

2021 ◽  
Author(s):  
Benke Xu ◽  
Yun He ◽  
Lian Liu ◽  
Guosheng Ye ◽  
Lulu Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Spatial Memory ◽  
Amyloid Beta ◽  
Dendritic Spines ◽  
Wheel Running ◽  
Synaptic Proteins ◽  
Aβ Peptides ◽  
People With Dementia

Abstract Background: Memory loss is the key symptom of Alzheimer's disease (AD). As successful drug treatments have not yet been identified, non-pharmaceutical intervention, such as physical exercise has been recognized as an effective strategy to improve memory function of people with dementia. Here we investigated the effect of prolonged physical running on hippocampal-dependent spatial memory and underlying mechanisms in 3xTg-AD mouse, a well-established rodent model of Alzheimer's disease (AD). Methods: 3xTg-AD transgenic mice with three AD mutations were used and compared with non-transgenic mice. Voluntary wheel running continued for 5 months (1 hour per day, 5 days per week) and was followed by spatial memory testing. At the end of behavior testing, dendritic spines, synapses, and synaptic proteins as well as amyloid-beta (Aβ) pathology were analyzed in the dorsal hippocampi. Results: Running improved hippocampal-dependent spatial memory in 3xTg-AD mice. This running strategy prevented both thin and mushroom-type spines on CA1 pyramidal cells in 3xTg-AD mice, whereas the effects of running in non-transgenic mice were limited to thin spines. The enormous effects of running on spines were accompanied by increased synapses and higher expressions of synaptic proteins. Notably, running downregulated the processing of amyloid precursor protein, resulting in reduced Aβ peptides, and spatial memory performance correlated with levels of Aβ peptides Aβ1-40 and Aβ1-42. Conclusion: These data suggest that prolonged running may improve memory in preclinical AD via slowing down amyloid pathology and preventing loss of synaptic contacts.

Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease

2002 ◽  
Vol 38 ◽  
pp. 37-49 ◽  
Author(s):  
Janelle Nunan ◽  
David H Small
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Alternative Pathway ◽  
Protein A ◽  
Proteolytic Processing ◽  
Gamma Secretase ◽  
Amyloid Beta Protein ◽  
Protein Precursor ◽  
Amyloid Beta Protein Precursor

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

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