Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by synaptic loss that leads to the development of cognitive deficits. Synapses are neuronal structures that play a crucial role in memory formation and are known to consume most of the energy used in the brain. Interestingly, AMP-activated protein kinase (AMPK), the main intracellular energy sensor, is hyper-activated in degenerating neurons in several neurodegenerative diseases, including AD. In this context, we asked whether AMPK hyper-activation could influence synapses' integrity and function. AMPK hyper-activation in differentiated primary neurons led to a time-dependent decrease in pre- and post-synaptic markers, which was accompanied by a reduction in synapses number and a loss of neuronal networks functionality. The loss of post-synaptic proteins was mediated by an AMPK-regulated autophagy-dependent pathway. Finally, this process was also observed in vivo, where AMPK hyper-activation primed synaptic loss. Overall, our data demonstrate that during energetic stress condition, AMPK might play a fundamental role in the maintenance of synaptic integrity, at least in part through the regulation of autophagy. Thus, AMPK might represent a potential link between energetic failure and synaptic integrity in neurodegenerative conditions such as AD.
Highlights
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly
Primary neurons were maintained up to 31 days in vitro (DIV), and the expression levels of AMPK subunits, pre- and post-synaptic proteins were assessed by Western blotting (WB) and immunocytochemistry (ICC)
An increased expression of the pre-synaptic proteins SYP, SNAP25, and Munc was observed during the first 17 days of differentiation, which remained stable up to 31 DIV, except for SNAP25 whose expression decreased after 27 DIV (Fig. 1a, c)
Summary
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. AD symptoms include progressive memory and cognitive functions impairment, which result from synaptic loss that occurs during the disease progression[1,2]. Synaptic loss is largely reported both in post-mortem human AD brain tissues[3], as well as in brain of AD mouse models[4]. A recent study investigated synaptic density in vivo in AD patients with synaptic vesicle glycoprotein 2A This study showed that AD patients displayed a reduction in the SV2A-PET signal in the hippocampus, a decrease that remained significant even after correction for atrophy and that correlated with episodic memory score[5]
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