Reduced expression of the cell intrinsic clock protein Bmal1 in myeloid cells accelerates cognitive decline and alters microglial function in aging mice

The circadian clock system plays a fundamental role in the temporal coordination of the external environment with internal physiological processes. These processes include the sleep/wake cycle, feeding, liver function, kidney function, core body temperature, including insulin release and heart rate, and immune function. With aging, the ability to rhythmically regulate these processes progressively declines. Furthermore, aging is associated with a chronic inflammation that is linked to multiple age-associated diseases, including cognitive decline. Several studies have demonstrated that deletion of Bmal1, a transcription factor and principal driver of cell-autonomous circadian rhythms, accelerates the aging process, exhibiting a variety of age-related diseases including sarcopenia, cataracts, organ shrinkage, bone calcification, and impaired glucose metabolism. Here, we show that myeloid-lineage specific knockdown of Bmal1 increases systemic inflammation and accelerates cognitive decline in aging mice. This was associated with a paradoxical increase in IBA1 expression and number of microglia with less morphological complexity and reduced lysosomal CD68 in the CA1 hippocampal region. Looking at individual microglia showed less CD68 in the Bmal1-deficient microglia, suggesting lysosomal dysfunction. Furthermore, myeloid Bmal1 deletion led to significant increases in pre- and post-synaptic proteins in aged mice, as well as decreased levels of C1q, which is required for synaptic pruning, suggesting impaired synapse clearance. In summary, our data indicates that Bmal1 knock-down in myeloid-lineage cells is sufficient to accelerate cognitive decline by a mechanism that may involve impaired synapse removal.