Voluntary wheel exercise improves learning and memory impairment caused by hippocampal Hb-α deficiency by reducing microglial activation and reversing synaptic damage.

Decreased hemoglobin (Hb) levels in peripheral blood may be a risk factor for Alzheimer's disease (AD). Hb-α is a monomeric form of Hb that exists in the central nervous system. Our previous RNA sequencing results revealed a decrease in the expression of the Hb-α gene in the hippocampus of AD model mice. However, the effects of Hb-α deficiency in the hippocampus on cognitive function and the underlying mechanism are unclear. Running exercise has been shown to improve cognition, but whether it can reverse the damage caused by Hb-α deficiency in the hippocampus needs to be further researched. In the present study, Mendelian randomization (MR) analyses revealed that lower levels of mean corpuscular Hb and Hemoglobin alpha 1 (HBA1) increased the risk of developing AD. When an adeno-associated virus (AAV) was used to knock down hippocampal Hb-α, the learning and memory ability of the resulting model mice decreased, similar to that of AD model mice. Moreover, the expression levels of advanced glycation end products (AGE) and their receptor (RAGE) were upregulated, microglia were activated, and the number of engulfed synapses increased, which damaged the number and structure of hippocampal synapses in the model mice. However, four weeks of voluntary wheel exercise effectively improved these conditions. In addition, we found that voluntary wheel exercise may compensate for Hb-α protein deficiency in the hippocampus by increasing the expression levels of Hb-α protein in plasma, cerebrospinal fluid, and other brain regions without altering Hb-α mRNA in the hippocampus of model mice. These results highlight the key role of Hb-α in hippocampal synaptic damage, elucidate the mechanism by which running exercise improves cognition by connecting the peripheral circulation and central nervous system through Hb-α, and provide new ideas for the diagnosis and treatment of AD.