Beta 2-adrenergic pathway combats Alzheimer's disease: Restoring cognition and synaptic integrity

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 β 2 -adrenergic receptor as a target through its regulation of synaptic plasticity, neuroinflammation, and epigenetic control. Activation of β 2 -adrenergic receptor potentiates long-term potentiation, reverses amyloid-beta-mediated synaptic loss, and stimulates neuroprotective gene expression through cyclic adenosine monophosphate-protein kinase A-cyclic AMP response element-binding protein. Moreover, β 2 -adrenergic receptor suppression of histone deacetylase 2/3 promotes transcriptional reprogramming, supporting synaptic function. Beyond synaptic maintenance, activation of β 2 -adrenergic receptor prevents neuroinflammation by polarizing microglia toward an anti-inflammatory phenotype and augmenting amyloid-beta degradation. Additionally, mitochondrial metabolism is regulated by β 2 -adrenergic receptor, diminishing oxidative stress and allowing for bioenergetic resilience. Enriched environments mediate their neuroprotective effects through, in part, activation of β 2 -adrenergic receptor, supporting its role in promoting synaptic resilience. Pharmacological activation of β 2 -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 β 2 -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 β 2 -adrenergic receptor is an appealing therapy for Alzheimer's disease. Future research needs to target optimizing brain-penetrant β 2 -adrenergic receptor agonists and determining their long-term effects on Alzheimer's disease pathology.