Beta 2-adrenergic receptor activation enhances neurogenesis in Alzheimer's disease mice

Impaired hippocampal neurogenesis is one of the early pathological features of Alzheimer＇s disease. Enhancing adult hippocampal neuro- genesis has been pursued as a potential therapeutic strategy for Alzheimer＇s disease. Recent studies have demonstrated that environmental novelty activates β2-adrenergic signaling and prevents the memory impairment induced by amyloid-β oligomers. Here, we hypothesized that β2-adrenoceptor activation would enhance neurogenesis and ameliorate memory deficits in Alzheimer＇s disease. To test this hypothe- sis, we investigated the effects and mechanisms of action of β2-adrenoceptor activation on neurogenesis and memory in amyloid precursor protein/presenilin 1 （APP/PS1） mice using the agonist clenbuterol （intraperitoneal injection, 2 mg/kg）. We found that β2-adrenoceptor ac- tivation enhanced hippocampal neurogenesis, ameliorated memory deficits, and increased dendritic branching and the density of dendritic spines, lhese effects were associated with the upregulation of postsynaptic density 95, synapsin 1 and synaptophysin in APP/PS1 mice. Furthermore, β2-adrenoceptor activation decreased cerebral amyloid plaques by decreasing APP phosphorylation at Thr668. These findings suggest that β2-adrenoceptor activation enhances neurogenesis and ameliorates memory deficits in APP/PS 1 mice.

Amyotrophic lateral sclerosis as a synaptopathy

The synapse is an incredibly specialized structure that allows for the coordinated communication of information from one neuron to another. When assembled into circuits, steady streams of excitatory and inhibitory synaptic activity shape neural outputs. At the organismal level, ensembles of neural networks underlie behavior, emotion and memory. Disorder or dysfunctions of synapses, a synaptopathy, may underlie a host of developmental and degenerative neurological conditions. There is a possibility that amyotrophic lateral sclerosis may be a result of a synaptopathy within the neuromotor system. To this end, particular attention has been trained on the excitatory glutamatergic synapses and their morphological proxy, the dendritic spine. The extensive detailing of these dysfunctions in vulnerable neuronal populations, including corticospinal neurons and motor neurons, has recently been the subject of original research in rodents and humans. If amyotrophic lateral sclerosis is indeed a synaptopathy, it is entirely consistent with other proposed pathogenic mechanisms – including glutamate excitotoxicity, accumulation of misfolded proteins and mitochondrial dysfunction at distal axon terminals(cortico-motor neuron and neuromuscular). Further, although the exact mechanism of disease spread from region to region is unknown, the synaptopathy hypothesis is consistent with emerging die-forward evidence and the prion-like propagation of misfolded protein aggregates to distant neuronal populations. Here in this mini-review, we focus on the timeline of synaptic observations in both cortical and spinal neurons from different rodent models, and provide a conceptual framework for assessing the synaptopathy hypothesis in amyotrophic lateral sclerosis.