Rapamycin protects against Aβ-induced synaptotoxicity by increasing presynaptic activity in hippocampal neurons

Ramírez, Alejandra E.; Pacheco, Carla; Aguayo, Luis G.; Opazo, Carlos

doi:10.1016/j.bbadis.2014.04.019

Cited by 21 publications

(14 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data collected by our studies support the key role of aberrant mTOR signalling in mediating the early progression of AD in DS population. Within this frame, the rescue of mTOR signalling by the administration of rapamycin, which has been previously tested in AD mouse models demonstrating favorable outcomes [ 19 , 27 , 29 – 31 , 78 – 81 ], represents a potentially valuable therapeutic strategy. Indeed, evidence obtained by the Oddo and Galvan laboratories [ 19 , 31 ] corroborated the positive effects of mTOR inhibition on hippocampal memory rescue in AD mice.…”

Section: Discussionmentioning

confidence: 99%

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Tramutola

Lanzillotta

Barone

et al. 2018

Transl Neurodegener

View full text Add to dashboard Cite

BackgroundDown syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression. Within this context, the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena. By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol (InRapa) that maximizes brain delivery and reduce systemic side effects.MethodsTs65Dn mice were administered with InRapa for 12 weeks, starting at 6 months of age demonstrating, at the end of the treatment by radial arms maze and novel object recognition testing, rescued cognition.ResultsThe analysis of mTOR signalling, after InRapa, demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR (reduced to physiological levels), which led, through the rescue of autophagy and insulin signalling, to reduced APP levels, APP processing and APP metabolites production, as well as, to reduced tau hyperphosphorylation. In addition, a reduction of oxidative stress markers was also observed.DiscussionThese findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis, thus ultimately resulting in improved cognition. Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals.Electronic supplementary materialThe online version of this article (10.1186/s40035-018-0133-9) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Tramutola

Lanzillotta

Barone

et al. 2018

Transl Neurodegener

View full text Add to dashboard Cite

show abstract

“…Enhanced synaptic activity was recently shown to be part of the protective mechanism exerted by rapamycin in models of AD. Rapamycin treatment increases levels of the presynaptic protein SV2 and the frequency of excitatory postsynaptic currents reducing Aβ oligomers synaptotoxicity (Ramírez et al, 2014 ).…”

Section: Functional Alterations In Alzheimer's Disease Brain: May Synmentioning

confidence: 99%

Synaptic activity and Alzheimer's disease: a critical update

Tampellini

2015

Front. Neurosci.

View full text Add to dashboard Cite

Synapses have been known for many years to be the crucial target of pathology in different forms of dementia, in particular Alzheimer's disease (AD). Synapses and their appropriate activation or inhibition are fundamental for the proper brain function. Alterations in synaptic/neuronal activity and brain metabolism are considered among the earliest symptoms linked to the progression of AD, and lead to a central question in AD research: what is the role played by synaptic activity in AD pathogenesis? Intriguingly, in the last decade, important studies demonstrated that the state of activation of synapses affects the homeostasis of beta-amyloid (Aβ) and tau, both of which aggregate and accumulate during AD, and are involved in neuronal dysfunction. In this review we aim to summarize the up-to-date data linking synaptic/neuronal activity with Aβ and tau; moreover, we also intend to provide a critical overview on brain activity alterations in AD, and their role in the disease's pathophysiology.

show abstract

“…Rapamycin, mTOR Inhibitor, is found to decrease the loss of synapse, reactive gliosis and neurodegeneration of perforant pathway in AD-tauopathy mouse model [99]. Also, it provides protection by increasing presynaptic activity in rat hippocampal primary neurons against Aβ-induced synaptotoxicity [100]. Further, chronic rapamycin use is shown to preserve brain vascular density, restore integrity and function through NO synthase activation in AD mouse brains [101].…”

Section: Discussionmentioning

confidence: 99%

Viral Induced Oxidative and Inflammatory Response in Alzheimer’s Disease Pathogenesis with Identification of Potential Drug Candidates: A Systematic Review using Systems Biology Approach

Talwar

Gupta

Kushwaha

et al. 2019

View full text Add to dashboard Cite

Alzheimer's disease (AD) is genetically complex with multifactorial etiology. Here, we aim to identify the potential viral pathogens leading to aberrant inflammatory and oxidative stress response in AD along with potential drug candidates using systems biology approach. We retrieved protein interactions of amyloid precursor protein (APP) and tau protein (MAPT) from NCBI and genes for oxidative stress from NetAge, for inflammation from NetAge and InnateDB databases. Genes implicated in aging were retrieved from GenAge database and two GEO expression datasets. These genes were individually used to create protein-protein interaction network using STRING database (score≥0.7). The interactions of candidate genes with known viruses were mapped using virhostnet v2.0 database. Drug molecules targeting candidate genes were retrieved using the Drug-Gene Interaction Database (DGIdb). Data mining resulted in 2095 APP, 116 MAPT, 214 oxidative stress, 1269 inflammatory genes. After STRING PPIN analysis, 404 APP, 109 MAPT, 204 oxidative stress and 1014 inflammation related high confidence proteins were identified. The overlap among all datasets yielded eight common markers (AKT1, GSK3B, APP, APOE, EGFR, PIN1, CASP8 and SNCA). These genes showed association with hepatitis C virus (HCV), Epstein-Barr virus (EBV), human herpes virus 8 and Human papillomavirus (HPV). Further, screening of drugs targeting candidate genes, and possessing anti-inflammatory property, antiviral activity along with suggested role in AD pathophysiology yielded 12 potential drug candidates. Our study demonstrated the role of viral etiology in AD pathogenesis by elucidating interaction of oxidative stress and inflammation causing candidate genes with common viruses along with the identification of potential AD drug candidates.

show abstract

Rapamycin protects against Aβ-induced synaptotoxicity by increasing presynaptic activity in hippocampal neurons

Cited by 21 publications

References 53 publications

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Synaptic activity and Alzheimer's disease: a critical update

Viral Induced Oxidative and Inflammatory Response in Alzheimer’s Disease Pathogenesis with Identification of Potential Drug Candidates: A Systematic Review using Systems Biology Approach

Contact Info

Product

Resources

About