Neuroinflammation in Alzheimer's disease pathway

The consensus among the research community is that Alzheimer’s disease (AD) is ultimately caused by the aggregation of misfolded amyloid beta (Aβ) and tau. However the Aβ/tau hypothesis doesn’t account for the entire disease pathology, and drugs developed to target Aβ have been relatively unsuccessful in improving disease outcomes. Since the 1990s, research has suggested that neuroinflammation contributes substantially to AD progression.

Neuroinflammation involves the activation of microglia and astrocytes, innate immune cells found in the brain. The blood-brain barrier usually protects the brain from the effects of inflammation, but damage (for example, by inflammatory species) can cause it to become more permeable, allowing cells like monocytes and macrophages to enter the brain. This means that, like the overall AD pathology, neuroinflammation is a self-sustaining, snowballing process.

There’s evidence to suggest that a sustained inflammatory response is present in AD: AD patient brains have increased inflammatory signaling markers¹, and AD markers like Aβ and tau have been found to positively correlate with inflammatory markers like TNF-α and interleukins in AD patient plasma².

It’s thought that the inflammatory mechanism of AD revolves around the activation of microglia. Aβ is thought to activate microglia chronically, and evidence suggests that tau aggregates also activate microglia³. Under normal conditions where they’re acutely activated, microglia play a key role in clearing Aβ and other debris by phagocytosis, but this performance is decreased in chronically activated microglia. This process is modulated by TREM2, a protein expressed on microglia that is involved in their response to amyloid plaques. Variants of TREM2 have found to be associated with AD symptoms, as loss of TREM2 function reduces the rate at which microglia clear amyloid plaques⁴.

 When activated, microglia produce and release pro-inflammatory cytokines like interleukins and TNF-α, as well as reactive oxygen species (ROS), all of which can disrupt normal synaptic functioning and cause cell death. The cytokines produced can also recruit other microglia, creating a cascade. The vicious cycle is completed as the pro-inflammatory mediators cause production of further Aβ oligomers, as well as more tau hyperphosphorylation, which in turn causes more microglial activation as well as the neuronal damage and cell death associated with Aβ and tau aggregates. The neuroinflammatory cycle can also damage the blood-brain barrier, accelerating the process further.