Inflammation is a biological response to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective mechanism and as a generic or innate response it doesn’t react to specific threats, but treats them all the same. Inflammation is a necessary element of the immune response and is normally closely regulated by the body, but when the inflammatory signals fails to switch off “chronic inflammation” results.
Chronic and even acute inflammation may be responsible for dementia, although it is not certain if it is a cause, contributor, or secondary phenomenon. That said, virally induced inflammation of the brain leads to Alzheimer’s-like changes. Head trauma results in immediate brain inflammation and an increased risk for later Alzheimer’s. Animal studies have linked immune reactions to neurodegeneration. In fact, rheumatoid arthritis (RA) patients over the age of 65 were more than twice as likely to suffer from Alzheimer’s. Inflammation of the gums has been linked with an increased risk for dementia. In short, brain inflammation (especially chronic inflammation), should be avoided.
The First Line of Defense
The blood brain barrier (BBB) separates circulating blood from the brain in order to keep out pathogens. The BBB will allow useful and necessary components such as water, some gases, and lipid-soluble molecules, as well as glucose and amino acids that are crucial to neural function.
Things you should know about BBB: (, Postdoctoral researcher @ UCSF)
- The impermeability of BBB results from tight junctions formed by cell adhesion proteins.
- Some small lipophilic molecules with appropriate charge and mass, can diffuse from blood into the CNS.
- Certain hydrophilic molecules (eg: glucose) use transporters present on luminal (blood) and basolateral (brain) side of the endothelial cells.
- Lipoproteins (eg: ApoE), use specific receptors (eg: LRP) that are highly expressed on the luminal side of the endothelium.
- These receptors help endocytose and transcytose certain compounds across the BBB.
The Second Line of Defense
On the protected side of the BBB, the brain’s immune cells patrol. Microglia are the macrophages of the central nervous system (CNS – the brain and spine). Like white blood cells on the other side of the BBB, they serve as the brain’s machrophages. This is particularly important because few antibodies are small enough to cross the blood–brain barrier, so the options to fight pathogens that do show up in the CNS are limited.
Tumor necrosis factor (TNF) is a proinflammatory cytokine released in large amounts by microglia as part of the so-called neuroinflammatory response associated with several neurological disorders including Alzheimer’s and Parkinson’s (Olmos and Lladó 2014). Unfortunately, TNF in turn activates microglia producing a feedback loop that probably prolongs neuroinflammation (Kuna et al. 2005). Furthermore, “in patients with Alzheimer’s disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology.” (Venegas et al. 2017)
Astrocytes are the other major immune response player on the brain side of the BBB. They secrete and recycle transmitters and are therefore neurosupportive. They also play a role in ion homeostasis, the regulation of energy metabolism, synapse repair, and modulate oxidative stress. As mind-boggling as it seems, one astrocyte may be responsible for up to 100,000 synapses (Halassa et al. 2007). Another fascinating little fact about astrocytes is that they are the primary producer of APoE in the brain. As noted above ApoE is crucial to transporting lipids across the BBB for use in cellular repair. For a discussion of ApoE 2 vs 3 vs 4 see At Risk for Alzheimer’s? Don’t Just Sit There! Moderate Exercise Protects the Brain.
Amyloid Beta Plaques
Much of the research on brain inflammation, as it relates to Alzheimer’s, predictably focuses on amyloid beta plaques. As stated earlier there is no clear cause and effect established, but we do know that Aß plaques are treated as a pathogen by both microglia and astrocytes with varying degrees of success. There are physical attempts to surround and isolate the Aß, processes to degrade the Aß, and a long list of actions and reactions involving expression and over-expression of inflammation-related factors.
When the BBB leaks it allows larger particles into the CNS. One bad guy that gets through is gram-negative bacteria with its LPS infused outer membrane. For more on this process see Gut Microbiota Reduced in Alzheimer’s. LPS is excitatory to astrocytes which become more reactive and begin to show immunoreactivity for the gamma secretase components presenilin-1 and nicastrin (Nadler et al. 2008). Presenilin-2 expression also appears in Alzheimer’s, but not in non-demented astrocytes (Takami et al. 1997).
Regardless of whether amyloid beta deposits cause inflammation or inflammation causes amyloid beta deposit (both are true by the way), the resulting feedback loop is a big problem and probably why so much effort has focused on finding a way to break the cycle and return the system to homeostasis.
Technically speaking – tau protein in paired helical filaments is hyperphosphorylated, truncated, and aggregated. Simply put, it’s tangled. These neurofibrillary tangles were first described by Alois Alzheimer in one of his patients suffering from the eponymous disease, so the symptom/cause has been in the literature since around 1906 if not on people’s minds (so to speak). At Dr. Alzheimer’s first academic presentation of his findings, most audience members were really there to hear the next speaker discuss “compulsive masturbation” so few paid attention to Alzheimer that day.
Tau pathology, like AB plaques, is either a cause or effect of neuroinflammation.
Aspirin, Enbrel, and Olive Oil
A 2012 Swedish study looked at aspirin as a preventative for Alzheimer’s. “Women on regular low-dose ASA (aspirin) declined less on the MMSE at follow-up than those not on ASA. This difference was even more pronounced in those who had ASA at both examinations compared with never users. All other cognitive tests showed the same trends. There were no differences between the groups regarding short-term risk for dementia.”
A study from 2016 found that the anti-inflammatory drug etanercept (marketed as Enbrel) taken for rheumatoid arthritis significantly reduced the risk of developing Alzheimer’s.
In a 2017 study, Temple University researchers showed that “the consumption of extra-virgin olive oil protects memory and learning ability and reduces the formation of amyloid-beta plaques and neurofibrillary tangles in the brain. We found that olive oil reduces brain inflammation but most importantly activates a process known as autophagy…the process by which cells break down and clear out intracellular debris and toxins, such as amyloid plaques and tau tangles.”
A Multi-pronged Solution
The studies highlighted here show promise for preventing and/or reversing Alzheimer’s pathologies and are probably part of a larger solution.
I’m sure that the coming weeks and months will produce more interesting results in the research around Alzheimer’s and inflammation and I’ll try my best to keep up.