Dopamine vs Alzheimer’s

One of the key hallmarks of Alzheimer’s disease is the formation of hardened beta-amyloid plaques around neurons. The beta-amyloid peptides themselves are supposed to be in the brain, but the hardened pieces of them that form the plaques are not.

While the full nature of the relationship between those plaques and Alzheimer’s disease is not known for sure (there are likely other factors involved, and “the amyloid hypothesis” is at this stage nominally just that, a hypothesis), one thing that has been observed is that increasing or reducing the plaques increases or reduces (respectively) Alzheimer’s symptoms such as memory loss.

Neprilysin

There is an enzyme, neprilysin, that can break down those plaques.

Neprilysin is made naturally in the brain, and/but we cannot take it as a supplement or medication, because it’s too big to pass through the blood-brain barrier.

A team of researchers led by Dr. Takaomi Saido genetically manipulated mice to produce more neprilysin, and those mice resultantly experienced fewer beta-amyloid plaques and better memory in their old age.

However wonderful for the mice (and a great proof of principle) the above approach is not useful as a treatment for humans whose genomes weren’t modified at our conception in a lab.

Since (as mentioned before) we also can’t take it as a medication/supplement, that leaves one remaining option: find a way to make our already-existing brains produce more of it.

The team’s previous research allowed them to narrow this down to “there is probably a hormone made in the hypothalamus that modulates this”, so they began experimenting with making the mice produce more hormones there.

The DREADD switch

DREADDs, or Designer Receptors Exclusively Activated by Designer Drugs, were the next tool in the toolbox. The scientists attached these designer receptors to dopamine-producing neurons in the mice, so that they could be activated by the appropriate designer drugs—basically, allowing for a “make more dopamine” button, without having to literally wire up the brains with electrodes. The “button” gets triggered instead by a chemical trigger, the designer drug. You can read more about them here:

DREADDs for Neuroscientists: A Primer

The result was positive; when the mice made more dopamine, the result was that they also made more neprilysin. So far, the hypothesis is that the presence of dopamine upregulates the production of neprilysin. In other words, the increased neprilysin levels were caused by the increased dopamine levels (the alternatives would have been: they were both caused by the same thing—in this case that’d be the DREADD activation—or the increase was caused by something else entirely that hadn’t been controlled for).

As to how the causal relationship was determined…

“But I don’t have (or want) a DREADD switch in my head”

Happily for us (and probably happily for the mice too, because dopamine causes feelings of happiness), the experiments continued.

This time, instead of using the DREADD system, they tried simply supplementing the mouse food with l-dopa, a dopamine precursor. L-dopa is often used in the treatment of Parkinson’s disease, because the molecules are small enough to pass through the blood-brain barrier, and can be converted to full dopamine inside the brain itself. So, taking l-dopa normally raises dopamine levels.

The results? The mice who were given l-dopa enjoyed:

• higher dopamine levels
• higher neprilysin levels
• lower beta-amyloid plaque levels
• better memory in tests

The next step for the researchers is to investigate how exactly dopamine regulates neprilysin in the brain, but for now, the relationship between l-dopa consumption and the reduction of Alzheimer’s symptoms seems clear.

You can read about the study here:

The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain

Is there a catch?

L-dopa has common side effects that are not pleasant; the list begins with nausea and vomiting, and continues with things that one might expect from having “too much of a good thing” when it comes to dopamine, such as dyskinesia (extra movements) and hallucinations.

You can read about it more here at the Parkinson’s Foundation:

Parkinson’s Foundation | Levodopa

However! All is not lost. Rather than reaching for the heavy guns by taking l-dopa unnecessarily, there are other dopamine precursors that don’t have those side effects (and are consequently less restricted, to the point they can be purchased as supplements, or indeed, enjoyed where they occur naturally in some foods).

Top of the list of such safe* and readily-available dopamine precursors is…

N-Acetyl L-Tyrosine (NALT): The Dopamine Precursor & More

If you’d like to try that, here’s an example product on Amazon… Or you could eat fish, white beans, tofu, natto, or pumpkin seeds 😉

*Quick note on safety: “safe” is a relative term and may vary from person to person. Please speak with your own doctor to be sure, check with your pharmacist in case of any meds interactions, and be especially careful taking anything that increases dopamine levels if you have bipolar disorder or are otherwise prone to psychosis of any kind. For most people, this shouldn’t be an issue as our brains have a built-in mechanism for scrubbing excess dopamine and ensuring we don’t end up with too much, but for some people whose dopamine regulation is not so good in that regard, it can cause problems. So again, speak with your doctor to be sure, because we are not doctors, let alone your doctor.

Lastly…

If you’d like an entirely drug-free approach, that’s skipping even the “nutraceuticals”, you might enjoy:

Short On Dopamine? Science Has The Answer

Take care!