Table of Contents
Treating Alzheimer’s disease: where to look for?
treatment and prevention
Treating Alzheimer’s disease: where to look for?
Besides cancer, Alzheimer’s decease is one of the major unsolved problems of modern world. It is not the major cause of death and less widespread then diabetes or heart diseases, or even HIV. But in all mentioned cases medicine knows how to deal with the symptoms to provide well-being and long lifespan.
So, what about for Alzheimer’s decease? Basically we still do not know either how to treat this disease or its’ origin.
Also the three main hypothesis of its drug development have always been amyloid hypothesis, tau hypothesis and cholinergic hypothesis, with the failure of each drug the picture gets more complicated.
This drug design is based on the assumption that amyloid is the key player of the disease. Amyloid plaques in the brain tissue is a golden standard for diagnosing whether patient’s dementia is due to Alzheimer’s disease or not.
Amyloid beta peptide (Aβ) as the main component of the amyloid plaques; thus is treated as the major target. This protein originates from the amyloid precursor protein (APP) via cleavage by the by β-secretase (BACE1) and intramembranous protease — γ-secretase. The Aβ does not form if α-secretase cleaves APP before BACE1 could.
So, the obvious solution was to develop α-secretase enhancers or β-secretase inhibitors, even though the role of β-secretase is still uncler. Since developing a protein structure capable of BACE1 inhibition is a complex task the perfect candidate is still being looked for. Recent works suggest combining the globules with metal chelation.
Also there are some works about γ-secretase inhibitors and modulators, but this is more dangerous path since γ-secretase is also involved in dominant cleavage process. Besides γ-secretase itself, its catalytic subunits presenilins could also be modulated.In addition to, cystein protease Cathepsin B works similar to β-secretase, so there is another possible target for inhibition.
And some studies show the potentially interesting usage of amyloid degrading enzymes, such as metalloenzyme neprilysin. But the usage of neprilysin is limited, considering its low specificity and potential disruption of other pathways due to degradation of other proteins.
The second marker of Alzheimer’ s desease is the tau-protein tangles in the brain. Normally, tau connects to microtubules and stabilizes neuronal axons, relaxing only for mitosis in young neural cells, but in different tauopathies it aggregates and causes the nearby neural death.
Several drugs are being developed targeting the tau inself or its alternative splicing products.
It is a relatively old observation that amyloid plaques affect cholinergic neurons secreting acetylcholine. Assuming that the decreasing concentration of acetylcholine is the reason for cognitive and memory impairment, the drugs of choice should compensate the loss. Majority of modern drugs prescribed to patients with Alzheimers’s are acetylcholinesterases inhibitors (donepezil, galantamine, tacrine, rivastigmine).
Do these drugs actually work as we wish ? There are doubts about it. That is why we need novel theories.
We all know that everything is interconnected, especially in brain. So do why we focus only on acetylcholine?
Some other neurotransmitters have been shown to take part in Alzheimer's neuronal pathology, such as GABA and glutamate, serotonin and norepinephrine. There are also results concerning dopamine involvement., basically in cholinergic modulation.
Besides, the major concern with the patients is the cognitive functions decline. So, some additional measures could be used for the neuroprotection and plasticity stimulation, e.g electrical/magnet brain stimulation.
Another point of view I first heard about on professor Carl Herrup’s lecture at HKUST, and it was quite unusual. He, as some of the other researches, questions amyloid cascade theory, implying that there was still dementia even after anti-amyloid antibody therapy on humans, and also certain number of human population does have Aβ aggregations, but does not have Alzheimer’s disease symptoms. The hypothesis he follows is about cell cycle. Basically, the mature neurons are trying to divide while normally, of course, they do not. To support this point, it was found in several studies that the disruption in Wnt/β-catenin signalling, which is a key pathway modulating the balance between neural stem cells proliferation and differentiation.
GSK-3β phosphorylates the glycogen synthase (GS). Interestingly, it is also involved in several major processes connected to neurodegeneration in Alzheimer’s. It regulates Wnt signaling, phosphorylates τ-protein and affects Aβ concentration in the brain. That is why several scholars already mention GSK3 theory as an plausible way to explain all mechanisms involved. Targeting GSK3β/β-catenin is another path to potential drug development.
Neuroinflammation is an ongoing process in Alzheimer’s decease and many other neurological deceases as well.
The mechanism involves chronic microglial activation via CD40-CD40L pathway. So, the membrane-bound CD40 and its cognate ligand (CD40L) interaction stimulates pathological APP cleavage.
So, why not to try anti-inflammation drugs? Actually we already do. Turns out that some acetylcholinesterase inhibitors are also anti-inflammatories, so the story has come full circle.
There are doubts in anti-inflammation efficacy on the moderate and late stages of Alzheimer’s, but it can be explained. Different drugs have anti-inflammatory mechanisms. The most effective for the symptom alleviation and even for the delay of the decease onset are prostanglandin (COX-2-mediated PGE2) inhibitors, including aspirin. od of also they can delay the onset of the disease.
Another important cells in neuroinflammation are platelets. It has been known for quite a while that platelets are not just for clots. Platelets’ vesicles contain a whole range of substances, including neurotransmitters, cytokines, growth factors etc. They also contain APP and CD40L, which makes them one of the key players in Alzheimer’s disease. It is shown, that during neuroinflammation there is a disruption of blood-brain barrier (BBB), and platelets can actually interact with neurons directly via membrane gangliosides.
However, the usage of anti-platelet agents can cause gastro-intestinal bleeding and other vascular problems. By the way, aspirin is also antiplatelet agent, so it’s usage for Alzheimer’s disease prevention is not common due the risk of serious side-effects.
Salicylic acid, the breakdown product of aspirin, has also been found to bind with GAPDH, preventing it to get into the cell, so it also prevents neuronal death affecting cell cycle regulation.
Another possible solution both for inflammation and protein aggregation is immunomodulation and anti-bodies treatment, which are also being considered now.
Patients with type-2 Diabetes Mellitus (DM-2) have a higher risk of acquiring amyloid plaques. But also pioglitazone, an anti-diabetic drug with hypoglycaemic action, could be used as drug for delay. This drug has been proposed and tested in the TOMMORROW project. The name derives from TOMM4 gene, which together with АроЕ – another possible pro-Alzheimer’s gene, — delays Alzheimer’s onset . ApoE protein mediates cholesterol metabolism, and high cholesterol level is also a risk factor for the disease.
As part of the bigger picture, it supports metabolic syndrome hypothesis of the disease. Cholesterol lowering agents (statins) and a diet rich in fish could also be beneficial, though the role of cholesterin in Alzheimer remains controversial.
Highly controversial, but a very popular theory highlights an oxidation damage of the cells as a major aging cause. The age is a major risk factor of Alzheimer’s onset. So, for for modulation of oxidative stress antioxidants were suggested. Vitamins C and E are a well-known anti-oxidants, though it is hard to believe that they would help when the Alzheimer’s is already diagnosed.
Anyway, they could be used as a prevention (or delaying) measure, if the oxidation theory is correct. Fruit-reach diet contain vitamins and also flavonoids, natural anti-oxidants. And it leads us to another potential source of the anti-Alzheimer’s drugs.
Since the Nobel prize for Artemisinin, derived from Artemisia annua widely used in Chinese medicine, conventional medicine became more interested in traditional medicine.
Even sceptics like me cannot argue with a wide range of drugs discovered from natural sources. For example, chewing willow bark (also used in Chinese medicine) contains Salicin, has been known as anti-fever measure, which led to Aspirin discovery.
There are some proposed drugs, derived from plants, like ginseng saponins from Ginsenosides, and phytoestrogens from liquorice (shown to modulate GAPDH).
There are two substances I want to highlight. On of them — tanshinone, derived from Salvia miltorrhiza. It is involved in different pathways, such as binding to estrogen receptors, glutamate system regulation and acetylcholinesterase inhibition. All these mechanisms can be beneficial if not for treatment but at least for dealing with symptoms of Alzheimer’s’.
And another underestimated drug is cannabinoid. Delta9-Tetrahydrocannabinol is shown to reduce microglial activation acting via CD40-CD40L pathway. It also affects GAPDH induced autophagy and cell proliferation. I think that the cannabinoid drugs have not got much attention until recent because of the strict laws concerning cannabis and marijuana as addictive substances. Interestingly, cannabis is also one of the fundamental herbs in traditional Chinese medicine.
treatment and prevention
It seems that circadian rhythms regulation plays an important role in Alzheimer’s onset. has been shown recently, that insufficient sleep is one of the risk factors of the disease. Interestingly, microglia could be involved – it clears the brain from debris during the night-rest hours. Alzheimer’s disease patients have problems with night insomnia and day sleepiness. To alleviate sleep problems light therapy is currently used.
Another risk factor is gender. Since women have a higher incidence of the disease, estrogen replacement therapy is suggested in post-menopausal period.
Just a quick glance on other risk factors and possible intervention.
1. high blood pressure: antihypertensive therapy
2. stress, depression: cognitive-behavioural therapy and anti-depressants (possibly)
3. insufficient physical activity and motor skills: using computers, knitting, playing musical instruments are shown to delay Alzheimer’s onset.
In this short review we talked about different old and new hypotheses of Azheimer’s disease. It brought us to a a wide range of promising targets. And the possible ways in drug discovery range from enhancing secretase-inhibitors to exploring natural components.Since Alzheimer’s disease is a complex pathology nearly every major pathway could be involved.
It is much to be done to actually find a drug treating the decease, but it is also important to find environmental and internal factors that actually cause it. Since the best way to treat the illness is to prevent it.
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 In modern developed countries. Parasite and other tropical diseases which are more widespread and possibly easier to treat are basically neglected.
 And by inhibiting β-Secretase we will possibly switch off some important process in our brain, like myelination.
 Some of the risk factors of Alzheimer’s — e.g., traumatic brain injury — also disrupt BBB.
 A good warning for those who work late hours, especially in science.
 Though in average they also live longer.