Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors.
Silvia Viana da SilvaMatthias Georg HaberlPei ZhangPhilipp BethgeCristina LemosNélio GonçalvesAdam GorlewiczMeryl MalezieuxFrancisco Q GonçalvesNoëlle GrosjeanChristophe BlanchetAndreas FrickU Valentin NägerlRodrigo A CunhaChristophe MullePublished in: Nature communications (2016)
Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimer's disease (AD). In the APP/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients.
Keyphrases
- mouse model
- induced apoptosis
- early stage
- protein kinase
- working memory
- cell cycle arrest
- end stage renal disease
- traumatic brain injury
- signaling pathway
- clinical trial
- newly diagnosed
- ejection fraction
- cerebral ischemia
- chronic kidney disease
- cell proliferation
- oxidative stress
- liver failure
- squamous cell carcinoma
- randomized controlled trial
- endoplasmic reticulum stress
- prognostic factors
- study protocol
- phase iii
- radiation therapy
- respiratory failure
- patient reported outcomes
- hepatitis b virus
- mechanical ventilation
- neoadjuvant chemotherapy
- extracorporeal membrane oxygenation
- smoking cessation
- acute respiratory distress syndrome