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!

10almonds Gets Hairy

Hair loss is a thing that at some point affects most men and a large minority of women. It can be a source of considerable dysphoria for both, as it’s often seen as a loss of virility/femininity respectively, and is societally stigmatized in various ways.

Today we’re going to focus on the most common kind: androgenic alopecia, which is called “male pattern baldness” in men and “female pattern baldness” in women, despite being the same thing.

We won’t spend a lot of time on the science of why this happens (we’re going to focus on the remedies instead), but suffice it to say that genes and hormones both play a role, with dihydrogen testosterone (DHT) being the primary villain in this case.

We’ve talked before about the science of 5α-reductase inhibitors to block the conversion of regular testosterone* to DHT, its more potent form:

One Man’s Saw Palmetto Is Another Woman’s Serenoa Repens…

*We all make this to a greater or lesser degree, unless we have had our ovaries/testes removed.

Finasteride

Finasteride is a 5α-reductase inhibitor that performs similarly to saw palmetto, but comes in tiny pills instead of needing to take a much higher dose of supplement (5mg of finasteride is comparable in efficacy to a little over 300mg of saw palmetto).

Does it work? Yes!

Any drawbacks? A few:

• It’ll take 3–6 months to start seeing effects. This is because of the hormonal life-cycle of human hairs.
• Common side-effects include ED.
• It is popularly labelled/prescribed as “only for men”

On that latter point: the warnings about this are severe, detailing how women must not take it, must not even touch it if it has been cut up or crushed.

However… That’s because it can carry a big risk to our unborn fetuses. So, if we are confident we definitely don’t have one of those, it’s not actually applicable to us.

That said, finasteride’s results in women aren’t nearly so clear-cut as in men (though also, there has been less research, largely because of the above). Here’s an interesting breakdown in more words than we have room for here:

Finasteride for Women: Everything You Need to Know

Spironolactone

This one’s generally prescribed to women, not men, largely because it’s the drug sometimes popularly known as a “chemical castration” drug, which isn’t typically great marketing for men (although it can be applied topically, which will have less of an effect on the rest of the body). For women, this risk is simply not an issue.

We’ll be brief on this one, but we’ll just drop this, so that you know it’s an option that works:

❝Spironolactone is an effective and safe treatment of androgenic alopecia which can enhance the efficacy when combined with other conventional treatments such as minoxidil.

Topical spironolactone is safer than oral administration and is suitable for both male and female patients, and is expected to become a common drug for those who do not have a good response to minoxidil❞

Read more: The Efficacy and Safety of Oral and Topical Spironolactone in Androgenetic Alopecia Treatment: A Systematic Review

Minoxidil

This one is available (to men and women) without prescription. It’s applied topically, and works by shortcutting the hair’s hormonal growth cycle, to reduce the resting phase and kick it into a growth phase.

Does it work? Yes!

Any drawbacks? A few:

• Whereas you’ll remember finasteride takes 3–6 months to see any effect, this one will have an effect very quickly
  • Specifically, the immediate effect is: your rate of hair loss will appear to dramatically speed up
  • This happens because when hairs are kicked into their growth phase if they were in a resting phase, the first part of that growth phase is to shed each old hair to make room for the new one
• You’ll then need the same 3–6 months as with finasteride, to see the regrowth effects
• If you stop using it, you will immediately shed whatever hair you gained by this method

Why do people choose this over finasteride? For one of three reasons, mainly:

• They are women, and not offered finasteride
• They are men, and do not want the side effects of finasteride
• They just saw an ad and tried it

As to how it works:

Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells

Some final notes:

There are some other contraindications and warnings with each of these drugs by the way, so do speak with your doctor/pharmacist. For example:

• Finasteride can tax the liver a little
• Spironolactone can reduce bone turnover
• Minoxidil is a hypotensive; this shouldn’t be an issue for most people, but for some people it could be a problem

There are other hair loss remedies and practices, but the above three are the heavy-hitters, so that’s what we spent our time/space on today. We’ll perhaps cover the less powerful (but less risky) options one of these days.

Meanwhile, take care!