Select Page



Neuroinflammation and Role of Microglial Impairment in Neurodegeneration

Neuroinflammation (a term that refers to any inflammation within the nervous system) is a central feature of Alzheimer’s disease (AD). Alzheimer’s-specific neuroinflammation results from the buildup of beta amyloid (Aβ) in the brain starting 10 to 20 years prior to a person showing any symptoms of AD and a malfunctioning cellular immune system1.

The brain has its own unique immune system comprised of microglia, which are similar to the macrophages found in the body’s general circulation outside the brain2.  Microglia play a central role in keeping the brain healthy.  They are small cells that migrate through the brain to detect and remove waste products by ingesting the debris.  Before the microglia detect debris, they travel through the brain in a resting non-active state.  When they detect debris, the microglia are activated to become phagocytic and are identified as having an M2 phenotype3.

Microglia can become harmful when they overproduce toxic cytokines, excitatory amino acids, and reactive oxygen intermediates, which results in neuroinflammation.  These microglia are identified as microglia inflammatory, or M1, phenotype3.

In healthy people, the equilibrium between the M2 and M1 phenotypes is maintained by the brain’s immune system.  However, this balance can be altered by stress signals3.

Scientists only recently discovered the important role regarding the imbalance of M1 and M2 phenotypes play in AD1.  By studying the genetics of large patient populations, scientists identified specific gene defects that are related to microglia activation.  People who have these specific gene defects have the level of risk of developing AD as do people who have the more common and well-known Apolipoprotein E (ApoE) gene4.

The “Amyloid Hypothesis”5 theorized the accumulation of Aβ plaque in the brain tissue resulting from poor clearance (or more rarely over-production) initiates a sequence of events starting with inflammation that ultimately lead to AD dementia.  That hypothesis is being re-evaluated due to the realization that the microglial impairment which causes the switch from M2 to M1 is what drives Aβ accumulation and promotes inflammation in the brain.  So, when Aβ begins to clump together in the brain, microglia sense this as a stress signal and migrate to ingest the Aβ clumps.  However, if the microglial are working sub-optimally because of a gene defect or because they are simply overwhelmed with debris, their ingestion rate is reduced, which leads to more Aβ accumulation.  At the same time, the impaired microglial are overproducing inflammatory molecules, which leads to more inflammation.  The combined effect of reduced phagocytosis and increased inflammation causes other pathological changes leading to irreversible damage to nerve cells1,6. AD is not the only disease in which microglial impairment is implicated. Neuroinflammation resulting from defective microglia is also evident in many other neurodegenerative disease such as such as Parkinson’s disease7,8, ALS9, Huntington disease10, and JNCL11.

The interest in microglia is stimulating scientists to find compounds that can increase the M2 phenotype’s ability to eliminate the Aβ plaques as they are formed while also reducing the inflammatory actions of the M1 phenotype (

CereSpir has capitalized on this new understanding of microglia’s role in AD and Batten disease and is believed to have the most advanced compound in development that primarily acts as a microglia modulator12,13, thereby potentially harnessing the brain’s own immune system to fight AD.



  1. Gandy et al., “CR1 and the “Vanishing Amyloid” Hypothesis of Alzheimer’s Disease”; Biological Psychiatry, Volume 73, Issue 5 , Pages 393-395 , 1 March 2013
  2. T. Town et al “The Microglial “Activation” Continuum: from Innate to Adaptive Responses”; Journal of Neuroinflammation (2005), 2:24;
  3. T.M. Weitz and T. Town “Microglia in Alzheimer’s Disease: It’s All About Context”; International Journal of Alzheimer’s Disease (2012), Article ID 314185, 11 pages;
  4. A. Boutajangout and T. Wisniewski “The Innate Immune System in Alzheimer’s Disease”; International Journal of Cell Biology Volume(2013), Article ID 576383, 7 pages;
  5. J.A. Hardy, G.A. Higgins “Alzheimer’s disease: the amyloid cascade hypothesis”; Science (1992) Apr 10;256(5054):184-5
  6. S. Gandy, F.L. Heppner, “Microglia as dynamic and essential components of the amyloid hypothesis”; Neuron. 2013 2013 May 22;78(4):575-7. doi: 10.1016/j.neuron.2013.05.007
  7. Lynda et al., Mediators of Inflammation 2012: (2012), Article ID 401264
  8. Tanaka et al., Journal of Neuroinflammation 2013, 10:143  doi:10.1186/1742-2094-10-143
  9. Frakes et al., Neuron Volume 81, Issue 5, p1009–1023, 5 March 2014
  10. Ellrichmann et al., Clinical and Developmental Immunology 2013: (2013), Article ID 541259, 11 pages
  11. Xiong and Kielian, J. Neurochem. 2013 127: 245-258
  12. V. Porrini et al “CHF5074, in Clinical Development for Treatment and Prevention of Alzheimer’s Disease, Switches Cultured Microglia from M1 to M2 Activation State” ADPD Conference (2013a);
  13. J. Ross et al “CHF5074 Reduces Biomarkers of Neuroinflammation in Patients with Mild Cognitive Impairment: A 12-Week, Double-Blind, Placebo-Controlled Study” Current Alzheimer Research, (2013) 10 742-53;