Abstract: Alzheimer’s disease is typified by amyloid-beta oligomer-mediated synaptic disruption, neuroinflammation, and mitochondrial loss of function, culminating in cognitive decline. Recent evidence points toward the β2-adrenergic receptor as a target through its regulation of synaptic plasticity, neuroinflammation, and epigenetic control. Activation of β2-adrenergic receptor potentiates long-term potentiation, reverses amyloid-beta-mediated synaptic loss, and stimulates neuroprotective gene expression through cyclic adenosine monophosphateprotein kinase A-cyclic AMP response element-binding protein. Moreover, β2-adrenergic receptor suppression of histone deacetylase 2/3 promotes transcriptional reprogramming, supporting synaptic function. Beyond synaptic maintenance, activation of β2-adrenergic receptor prevents neuroinflammation by polarizing microglia toward an anti-inflammatory phenotype and augmenting amyloid-beta degradation. Additionally, mitochondrial metabolism is regulated by β2-adrenergic receptor, diminishing oxidative stress and allowing for bioenergetic resilience. Enriched environments mediate their neuroprotective effects through, in part, activation of β2-adrenergic receptor, supporting its role in promoting synaptic resilience. Pharmacological activation of β2-adrenergic receptor with specific agonists such as formoterol and clenbuterol has shown promise in preclinical models of Alzheimer’s disease by restoring cognitive function and synaptic integrity. In this review, the molecular mechanisms of β2-adrenergic receptor-mediated neuroprotection are examined, with specific emphasis on its regulation of synaptic plasticity, neuroinflammation, mitochondrial function, and epigenetic control. Due to its multi-faceted action for maintenance of neuronal health, activation of β2-adrenergic receptor is an appealing therapy for Alzheimer’s disease. Future research needs to target optimizing brain-penetrant β2-adrenergic receptor agonists and determining their longterm effects on Alzheimer’s disease pathology.

Key words: Alzheimer’s disease, amyloid-beta, β2-adrenergic receptor, DNA methylation, enriched environments, histone modification, long-term potentiation, microglia, microRNAs, mitochondria, neuroinflammation, synaptic plasticity