Brain-derived neurotrophic factor (BDNF) shows up in many aspects of the interaction between health practices, mechanisms of aging, and mechanisms of neurodegeneration. Most research is focused on the effects of BDNF on neural plasticity, meaning the generation of new neurons from neural stem cell populations, followed by the integration of those new neurons into neural networks, such that they participate in the functioning of the brain. Plasticity is necessary for memory, learning, and maintenance and repair of brain tissue, and in this context the presence of higher levels of BDNF appears to be entirely beneficial.
Unfortunately, BDNF levels decline with age, for reasons that are yet to be fully explored. Exercise is known to improve memory function in older individuals, and there is good evidence for increased BDNF to be an important mechanism in this effect. Similarly, gut microbes generate butyrate, which increases BDNF, establishing a link between changes in the gut microbiome and age-related cognitive decline. Various interventions that improve memory in old mice, such as upregulation of osteocalcin or RbAp48 have also been shown to produce their effects via increased expression of BDNF.
So why not just delivery BDNF as a therapy to improve cognitive function in later life? This does indeed work, as illustrated in today's open access research materials. Interestingly, the authors are focused on the effects of BDNF on inflammatory behavior in the immune cells of the brain rather than on neuroplasticity. It is becoming clear that chronic inflammation in brain tissue is an important contributing cause of neurodegenerative conditions. Among other process, chronic inflammation in the brain involves the inappropriate inflammatory activation of microglia, a specialized type of innate immune cell resident to the brain. Beyond the usual functions one would expect for such cells - chasing down pathogens, destroying errant cells, and so forth - microglia also aid in the maintenance of synaptic connections in various ways. So it is entirely plausible that more inflammatory microglia could mean a greater disruption of neural function in numerous ways, both via inflammatory signaling that changes cell behavior for the worse, and through neglect of normal microglial duties.
Microglial activation is implicated in the pathogenesis of multiple neurodegenerative diseases. Under physiological conditions, microglia are in a resting state characterized by ramified morphology, and they function as homeostatic keepers of the central nervous system. Resting microglia are not dormant; their processes are constantly and actively scanning a defined territory of brain parenchyma. After they have been exposed to stimulatory signals, microglia undergo various degrees of activation, such as changing their morphology, gene expression, and functional behavior. Depending upon the type, intensity, and duration of the exposure to the stimuli, activated microglia can be neuroprotective or neurotoxic. Activated microglia can release various inflammatory cytokines and toxins that together might injure or even cause neuronal death.
Brain-derived neurotrophic factor (BDNF), a versatile member of the neurotrophin family, is widely and highly expressed in the brain and is a chief regulator of axonal growth, neuronal differentiation, survival, and synaptic plasticity. In the central nervous system, BDNF and downstream prosurvival pathways have been demonstrated to protect neurons from damage and enhance neuronal network reorganization after injury. It has also been reported that BDNF treatment could reduce degrees of microglial activation in certain brain injury models, albeit these responses were considered a consequence of reduced neuronal injury and death elicited by BDNF. The direct effect of BDNF on microglia has rarely been explored.
This study aimed to characterize the role of BDNF in age-related microglial activation. Initially, we found that degrees of microglial activation were especially evident in the substantia nigra (SN) across different brain regions of aged mice. The levels of BDNF and TrkB in microglia decreased with age and negatively correlated with their activation statuses in mice during aging. Interestingly, aging-related microglial activation could be reversed by chronic, subcutaneous perfusion of BDNF. Peripheral lipopolysaccharide (LPS) injection-induced microglial activation could be reduced by local supplement of BDNF, while shTrkB induced local microglial activation in naïve mice. Thus in conclusion, decreasing BDNF-TrkB signaling during aging favors microglial activation, while upregulation BDNF signaling inhibits microglial activation via the TrkB-Erk-CREB pathway.