The mainstream view of Alzheimer's disease is that it begins with a slow increase in aggregation of amyloid-β, though the reasons why only some people exhibit high levels of amyloid-β are much debated. The amyloid-β then rouses the immune cells of the brain into inflammatory behavior and cellular senescence. The resulting chronic inflammation causes sufficient dysfunction to allow tau protein to alter and aggregate, and it is this aggregation that causes the widespread cell death and dysfunction in the later stages of the condition. Thus there is considerable interest in better understanding how amyloid-β causes this inflammatory behavior in immune cells, with an eye to potentially interfering in this mechanism. The brute force approach of destroying senescent cells in the brain has shown promise in animal studies, for example. The results here are more illustrative of the sort of investigative work presently taking place in the scientific community, however.
The classical hallmarks of Alzheimer's disease (AD) include the formation of amyloid-beta (Aβ) plaque deposits and neurofibrillary tangles (NFT) containing abnormal hyperphosphorylation of tau. The mechanisms triggering the deposition of the Aβ or the formation of NFTs are currently under investigation. However, several mechanisms and factors have been suggested to be involved in the initiation and the progression of the disease, including activation of the innate immune system, environmental factors and lifestyle. The innate immune system has been widely studied and has been implicated in several neurodegenerative diseases. Over the last few years, several studies have suggested that inflammation plays a major role in the initiation and progression of AD.
The inflammatory process in the central nervous system (CNS) is generally referred to as neuroinflammation. Glial cells have a leading role in propagating neuroinflammation. Among glial cells, microglia are considered the main source of proinflammatory molecules within the brain. It is believed that sustained release of proinflammatory molecules such as cytokines, chemokines, nitrogen reactive species (NRS) or reactive oxygen species (ROS) can create a neurotoxic environment that drives the progression of AD.
One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aβ plaques. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.