Norepinephrine vs Alzheimer’s Disease

Norepinephrine (or noradrenaline, in the rest of the world outside of the US), is a hormone and neurotransmitter generally associated with stress, fight-or-flight responses, and hypertension.

Like any of our hormones, it has its place, and we wouldn’t do well without it (same deal for cortisol, which has a very bad reputation, but again, we do need it or else we would not, for example, wake up in the morning).

When it comes to neurochemistry, a shortage of norepinephrine can result in lethargic listlessness, which is why some antidepressants work on the noradrenergic* system (as opposed to the more common SSRIs, which work on the serotonergic system), to boost flagging norepinephrine levels and perk us** up.

*Yes, it’s called that even in the US where the hormone/neurotransmitter itself is called norepinephrine rather than noradrenaline.

**this article brought to you by the power of this writer taking mirtazapine, a selective norepinephrine reuptake inhibitor (SNRI) antidepressant, that thus increases the amount of available norepinephrine in her brain.

So… How does it protect against Alzheimer’s disease?

Dialing down the brain’s immune system

Because of the blood-brain barrier, there are many things that happen either only inside of, or only outside of, our brain—which because of the unique nature of the brain’s anatomy, means that we often have a specialized system doing the same job inside the brain as a different system does outside of the brain, but in a different way.

See for example how the glymphatic system (a portmanteau of glial cells and lymphatic system) in the brain does approximately the same job as the lymphatic system does in the rest of the body:

How To Clean Your Brain (Glymphatic Health Primer) ← this helps protect us against Alzheimer’s, Parkinson’s, and other neurodegenerative conditions

And those glial cells? Some of them do the job otherwise done by parts of our immune system that can’t operate inside our brain.

Specifically, microglia do approximately the same job inside our brain as macrophages do outside of it: “eating” things that shouldn’t be there—ranging from actual invading pathogens, to bits of debris that are also in the way.

That our brain has an immune response is, generally speaking, a good thing. But much like the immune system in the rest of our body, things can get out of hand.

As with how chronic inflammation (and/or autoimmune disorders) causes problems in the rest of the body, neuroinflammation can cause problems in the brain—not least of all: it can lead to Alzheimer’s.

The microglia are involved in the cleanup of the β-amyloid proteins that can otherwise build up into harmful plaque resulting in neuronal damage and with it, neurodegeneration), so calming them down a bit means they can do their actual assigned job better for longer.

Dr. Ania Majewska et al. did a study into how norepinephrine’s inhibitory effect via β2 adrenergic receptors (β2AR) in microglia has an anti-inflammatory effect, and found that it has potential as an Alzheimer’s preventative.

In their words, “β2AR manipulations can alter disease pathology”, which is a great example of how carefully scientists say things, but the series of declarations adds up to the same; we’ll quote some points directly from the paper’s abstract:

• NE inhibits surveillance activity of microglia, the brain’s resident immune cells, via their β2 adrenergic receptors (β2ARs)
• Microglial β2AR signaling is an important modulator of amyloid pathology.
• Endogenous β2AR signaling degenerates as a function of amyloid pathology and aging.
• In AD, microglia downregulate β2AR expression early and progressively.
• β2AR manipulations can alter disease pathology.
• Importantly, dampening microglial β2AR signaling worsened plaque load and the associated neuritic damage, while stimulating microglial β2AR signaling attenuated amyloid pathology.
• Our results suggest that microglial β2AR could be explored as a potential therapeutic target to modify AD pathology.

Translating from sciencese (if you’ll pardon that we’ll still use some big words, but only ones we’ve already explained):

Norepinephrine activates certain receptors in microglia, and those receptors tell the microglia to “keep calm & carry on”. In the case of Alzheimer’s disease, those receptors stop working correctly, leading to increased neuroinflammation. Thus, stimulating those receptors with norepinephrine reduces neuroinflammation, allowing the microglia to calmly carry on with their actual job of getting rid of the amyloid that leads to Alzheimer’s disease.

You can read the paper itself here:

Noradrenergic signaling controls Alzheimer’s disease pathology via activation of microglial β2 adrenergic receptors

Want to learn more?

Check out:

• An Accessible New Development Against Alzheimer’s (Dopamine vs Alzheimer’s)
• How To Reduce Your Alzheimer’s Risk
• Take Care Of Your Lymphatic System To Beat Cognitive Decline
• What’s Your Vascular Dementia Risk?
• Alzheimer’s Causative Factors To Avoid

Take care!