Neuroinflammation – why it matters in Alzheimer’s disease

Currently there are few options for the treatment of Alzheimer’s disease (AD), with acetylcholinesterase (AChE) inhibitors only recommended for mild to moderate AD, memantine for moderate to severe AD, and no pharmacological treatments currently available for the early stages of the disease.1 But, as speakers at the latest European Academy of Neurology (EAN) congress held in Budapest were so keen to highlight, targeting neuroinflammatory pathways could be promising.2 Indeed, of the 87 agents currently in Phase II of clinical trials for the treatment of AD, 20% target neuroinflammation.3

20% of the 87 agents currently in Phase II of clinical trials for the treatment of Alzheimer’s disease target neuroinflammation3

Neuroinflammation and microglia

In the CNS, microglia are the resident immune cells of the brain. However, as well as serving a function as the macrophages of the CNS, the complex communication between microglia and neurons (together with a subtype of glial cells called astrocytes) plays a crucial role in the healthy formation and refinement of synapses.4

The normal neuroinflammatory responses need to be well controlled. Usually, they are beneficial and adaptive, and a balance of inflammatory and intrinsic repair processes influences functional recovery from injury.5 However, when there is a breakdown of communication between astrocytes and microglia, the resultant disruption to the usual neuroinflammatory response can have important negative consequences for neurodegenerative diseases such as AD.6


Microglia, their influence on Alzheimer’s disease and new opportunities for therapy

A key marker of Alzheimer’s disease is the accumulation of amyloid beta (Aβ) plaques in the brain. Indeed, in 95% of all cases of late-onset AD, plaque build-up is thought to be due to reduced clearance of Aβ. Microglia would normally be involved in limiting the build-up of Aβ, and it has been suggested that reduced clearance results from the aberrant function of microglia.

One mechanism by which this may occur is when the PIEZO1 calcium ion channel is blocked within the cells. In one study it was found that clinical activation of the PIEZO1 channel elicits a unique functional state in microglia which increases cell survival, motility and the rates of phagocytosis. This mechanism may be a potential route for AD treatment.7

Another area of interest concerns microglia and their role in synaptic pruning. It has been known since the early ‘90s that synapse loss has a strong correlation with cognitive impairment,8 and recently it has been discovered that microglia (which carry out synaptic pruning as part of healthy brain development) perform this role aberrantly in AD.9 The pruning mechanism is mediated by a complement cascade which is initiated by the protein complex C1q. Blocking C1q is associated with an increased level of synapses present in cases of early AD, and also protection against synaptic loss and cognitive impairment in mouse models.9 This could signify a potential treatment target not just in AD but potentially across a range of neurological diseases.

Yet another potential treatment option could be to target the microglial cells themselves. Disease-associated microglia overexpress gene Spp1, which triggers the phagocytic effect and instructs them to engulf synapses in the AD brain.10 So, by addressing this directly, it might be possible to limit the phagocytic activities of the microglia, thus addressing the depletion of neurons.

Targeting neuroinflammatory pathways offers new therapeutic opportunities in AD and across a range of neurological diseases

The clinical consequences of targeting neuroinflammation could be significant. There is evidence that by doing so disease progression can be slowed, cognitive decline can be reduced, and the risk of dementia can be decreased.2 However, there are still challenges that need to be addressed for new treatments to be developed. Issues include how to overcome the blood-brain-barrier, and how molecules can be designed to be brain-specific. There is also a great need to quantify when and where neuroinflammation happens in the brain. Identifying more biomarkers, such as glial fibrillary acidic protein (GFAP), which correlate to disease progression of AD will be vital in helping to evaluate treatment outcomes for these exciting new developments.11


This satellite symposium was supported by Novo Nordisk.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

  1. NICE Guidance NG97. Available at (Accessed 03 July 2023).
  2. A beginners guide to neuroinflammation and why it matters in Alzheimer’s disease. Online session at: 9th EAN congress; 2023 July 1; Budapest and virtual.
  3. Cummings J, et al. Alzheimer’s Dement. 2023;9:e12385.
  4. Vainchtein ID, et al. Trends Neurosci. 2020;43(3):144-54.
  5. DiSabato DJ, et al. J Neurochem. 2016;139 (Suppl 2):136-53.
  6. Garland EF, et al. Front Neurosci. 2022;16:824888.
  7. Jäntti H, et al. J Neuroinflammation. 2022;19(1):147.
  8. Terry RD, et al. Ann Neurol. 1991;30(4):572-80.
  9. Hong S, et al. Science. 2016;352(6286):712-16.
  10. De Schepper S, et al. Nat Neurosci. 2023;26(3):406-15.
  11. Kim KY, et al. Cells. 2023;12(9):1309.
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