Novel Drug Treatment for Alzheimer's Disease, a Future Hope.
Introduction
Around the world, there is a need to increase the expenditure in development and research of dementia (1). Statistically every 3 seconds one person is developing dementia which 60-70% of the cases are diagnosed as Alzheimer’s disease (AD) (1,2). Another worrying fact is that the number of people with AD will triple by 2050 (1). The latest World Alzheimer Report has demonstrated that there are not enough publications of neurodegenerative disorders and compared to cancer publications there is an astounding 1:12 ratio (1). It is also noted that there are not enough people going into dementia research.
Is this a worrying future?
See my previous blog on “An Introduction to Alzheimer's Disease with Its Normal Anatomy and Its Pathophysiology.”
Novel drug treatment
In terms of medications, there has not been any significant breakthrough in the past 40 years and there is no cure for AD (1). There are different approaches to alleviate AD and its symptoms. These treatments focus on sleep change, behaviour change, alternative medicine and most important medications for memory, intellect, rationality and social skills (3-6). Currently, there are only four drugs which are used in AD and these are the cholinesterase inhibitors (donepezil, rivastigmine and galantamine)(7) and memantine,(8) a partial antagonist of N-methyl-D-aspartate (NDMA) receptor (3). Novel drug researchers are using scaffolding with linker techniques, novel insights on old drugs and serendipity.
Dr Martin Morrissey from the Massive Open Online Course (MOOC) mentions that the cholinesterase inhibitors have modest potential benefits with only six months improvement on the patient’s trajectory with AD. It was also mentioned that only 3 patients out of 10 would show clear benefits (4,5). The reason for this is that the current medication (cholinesterase inhibitors and memantine) do not target the cause of the pathophysiology of AD but rather focus in increasing the neurotransmitters such as acetylcholine and reducing the destructive effects of too much glutamate by blocking its receptor.
The effectiveness of these medications are only modest in terms of improving cognition and lifestyle and that is if the patient can tolerate the unwanted side effects. The literature also mentions that depending on the person these medications may take a while to start showing potential benefits and may work for up to 3-5 years (to some people it may start immediately). However, there is uncertainty about the length of time as we can be confident that 6 months is the time given before the medication stops being efficacious. That is the unfortunate and harsh truth. The positive take on these medications is that it gives family more time to be prepared mentally, financially and start planning for the future as everyday matter.
We can all agree that there is a vital need for a breakthrough and new medications for AD. Hence, the importance of emphasising the ‘whole person focus’ care towards a patient diagnosed with AD is fundamental.
Therefore the main goals of AD drugs are to prevent neuron cell death, remove Aβ (beta-amyloid) proteins or aggregations, prevent neurofibrillary tangles, increase synaptic communication and interactions, and finally to reduce metal ions, radicals and reactive oxygen species (3-9).
Novel Drug Hybrid as a Potential Candidate (10)
A 2018 study has shown a potential drug using a two molecular scaffold technique with the multi-targets approach. This is done by reducing the acetylcholinesterase (AChE) enzyme and inhibiting the copper inducing Aβ protein aggregation with potential antioxidant activity and neuroprotection. The aim is to recover cholinergic neuron activity. As shown in Figure 1, the drug contains Tacrine (TAC), which was the first approved AChE inhibitor (11) and was selected as its main scaffold. TAC is attached through different linkers to Hydroxyphenylbenzimidazole (BIM).
Figure 1. The design of the TAC-BIM hybrids with its allocated linkers (10). This picture was modified from the Hiremathad A et al. Novel Tacrine-Hydroxyphenylbenzimidazole hybrids as potential multitarget drug candidates for Alzheimer's disease. https://doi.org/10.1016/j.ejmech.2018.02.023.
BIM is thought to have a potential desirable effect on hitting several targets for AD. The BIM moiety has a chelating nature which may conjugate with multiple roles. These could be for the inhibition of copper (Cu) that induced Aβ aggregation. The linker also plays a role as by choosing the right linker, it can potentially improve the favourable interaction with the AChE compared to using TAC on its own. Hiremathad et al (10) have run several docking simulations to test different TAC-BIM conjugates with different linkers in the aim to get the most effective, potent and desirable effects.
The pharmacokinetics of certain TAC-BIM conjugates seems to have potential desirable pharmacokinetic properties. These are to be able to cross the blood-brain barrier which is important in AD, to cross the intestinal tract to the blood circulation and not to break the Lipinski’s rule. TAC-BIM hybrids are eligible candidates for oral route drug administration. In conclusion, TAC-BIM hybrids have shown excellent activity as an AChE inhibitor and as a potential drug for AD. The three-methylene linker has shown the highest in inhibiting self and Cu-inducing Aβ aggregation by up to 75%. The hybrids chosen in the study have shown moderate antioxidant properties best shown with hydroxyl groups in the linkers. Some of the hybrids have also shown neuroprotective elements with neurotoxicity inhibition. Overall, Hiremathad et al (10) have demonstrated these hybridisation strategies to present potential in further development as multifunctional target activity as these hybrids are worthy for further stage development.
An Old Drug with Novel Insights (12,13)
There may be a new function for aspirin, a widely used and available drug, for the decreasing in Aβ plaques in AD. The autophagy-lysosome system removes the abnormal Aβ protein aggregation within the cell. It is highly regulated and is an essential degradation pathway. Autophagosomes, a doubled membrane vesicles, transports these plaques to lysosomes for degradation (14). In AD, there is a decrease in the lysosome capacity and an increase in autophagic vacuoles (15,16) with an accumulation in immature lysosome containing low degradation enzymes (17).
A recent 2018 study by Chandra et al (13) has studied the low dose effect of aspirin on lysosomal biogenesis which is crucial in removing and degrading Aβ plaques accumulation. It was found that low dose aspirin increased complicated lysosomal signals, markers and associated proteins to increase lysosomal biogenesis. It was noted that there was a boost in lysosomal numbers with increased functions of enzymes and an increase in autophagic vacuoles at different stages of maturation.
Aspirin does this by upregulating the Transcription Factor EB (TFEB) gene which is a major regulator of the autophagy-lysosomal pathway and is key in the lysosome biogenesis. Peroxisome Proliferator-Activated Receptor (PPAR-α), which regulates numerous genes as a transcriptor factor, is increased in activation activity by aspirin. PPAR-α binds to the Peroxisome Proliferator Responsive Element (PPRE) site as PPRE is the gene promotor of TFEB. Hence, the increase in PPAR-α activation will up-regulate TFEB protein production. Figure 2 demonstrates the pathway and the involvement of the TFEB gene with PPAR-α activation on PPRE.
Figure 2. Aspirin’s effect through the TFEB gene pathway in reducing Aβ pathology (12, 13).
There have been significant in vivo positive effects, by oral administration, with a dose of 2 mg/kg for 1 month which increased PPAR-α recruitment in mouse models. Aspirin was shown to increase levels in TFEB protein and there has been a significant reduction of Aβ plaques in the hippocampus in mice. However, how much does aspirin improve memory deficit by removing Aβ plaques is still unknown.
Interestingly, another 2018 study by Patel et al (18) has demonstrated that aspirin involvement with PPAR-α increased and improved the hippocampus plasticity and memory deficit in certain mice breed. These findings shed a light on aspirin’s usefulness and the reversal of lysosomal dysfunction through PPAR-α mediated up-regulation of TFEB. This was concluded to be positive in removing Aβ plaques in mice. Further studies should be conducted on this old drug with novel insights in humans.
A Sweet Serendipity Discovery Has Potential Multi-Hit in AD (9)
A recent 2018 study has demonstrated an FDA approved sweetener to be effective in vitro as an antioxidant, Beta-secretase 1 (BACE1) and amyloid plaque aggregation inhibitor and confirmed as a possible multi-target inhibitory drug for AD. Neohesperidin dihydrochalcone (NHD) is non-toxic and non-carcinogenic with neuroprotective effects (9).
Wang et al (19) mentioned that NHD is easily distributed in tissue and reaches Cmax within 5 minutes of administration in rats. The study also showed that NHD crossed the blood-brain barrier and could potentially indicate as a CNS drug for AD in humans (19). β-Amyloid Precursor Protein (APP) is a critical pathogenesis of AD and undergoes proteolysis to generate hydrophobic Aβ proteins. It is highly regulated (20). Aβ aggregates into a highly ordered β-sheets which is neurotoxic. BACE1 controls the rate-limiting step of APP proteolysis. In vitro assay has confirmed NHD potency and the binding to BACE1 which induces a conformational change of the protein.
Hence, there is no substrate recognition and NHD completely inhibits the activity of BACE1 at 500 nanomolar concentration. Instead of going towards the amyloidogenic APP processing the pathway goes towards the non-amyloidogenic APP processing making no insoluble Aβ proteins. It is seen in mice with knocked out BACE1 to lack Aβ production making BACE1 an important and potential therapeutic target (21). To this date, several BACE1 inhibitors have been reported and only a few are in phase III clinical trials (22)
It was found that the fibrils and the soluble oligomer showed neurotoxicity and that the pre-fibrillar aggregate of Aβ disrupted ion homeostasis (23) and increased in oxidative stress (24). The oxidative stress, through the oxidative modification of proteins, DNA, lipids and a large amount of redox-sensitive ion metals, up-regulates BACE1 and induces the proteolysis of APP. The outcome is an increase in Aβ protein abundance hence inhibiting the Aβ aggregation pathway as well as having an anti-oxidant property would be advantageous. NHD has been identified in silico as an anti-oxidant, BACE1 inhibitor and inhibits Aβ protein aggregation. This has been validated in vitro with neuroprotective activity. Figure 3 gives a summary of the NHD mode of action as a multi-target inhibitor for AD.
Figure 3. The mode of action of Neohesperidin dihydrochalcone (NHD) and its application in AD therapeutics (9). Amyloidogenic APP processing pathway has been changed and modified from BioLegend (25).
Conclusion
Out of the novel drugs for Alzheimer’s disease I have chosen only 3 as the research into the novel drug is very extensive and broad (although not as close to cancer drug research). The reason why I picked these examples is that I found it interesting to use a hybrid technique with a known drug that has a modifiable linker and to use drugs that have been on the market for decades (such as aspirin).
Alzheimer’s disease, the most common form of dementia, is a major public health concern. There are no cures for Alzheimer’s disease and there is a lack of medication that can stop the disease’s progression. Currently, there is only palliative therapy with patient-centred care approach. There is a lack of research, publications and funding in Alzheimer’s disease. However, scaffolding techniques with unique linkers which increase drug effectiveness, interesting new insights on old drugs and serendipity sheds a light of hope towards curing Alzheimer’s disease. Hopefully, more drugs can hit the market a make a difference in people’s lives as well as their families.
Abbreviations
Published 30th October 2019. Last reviewed 1st December 2021.
Reference
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