INTRODUCTION
In this editorial, we comment on progress in the drug treatment for Alzheimer's disease (AD). AD is a degenerative dementia that disrupts neurocognitive function. The underlying pathogenesis of AD is complex and is thus difficult to address through a single drug or intervention[1]. The effective treatment of AD faces many challenges, and current drugs essentially treat symptoms, assisting in the restoration of cognitive function and controlling abnormal behavior while retarding disease progression and associated deterioration. Despite decades-long research and development of drugs for AD, few have been officially approved for clinical use. The primary reasons are that the key factors triggering AD onset are still unclear, the targeting of single factors or molecules, poor drug bioavailability, poor penetration of the blood–brain barrier, and difficulties associated with nerve cell regeneration and functional recovery[2]. Although a comprehensive understanding of the molecular mechanisms underlying AD onset is as yet unavailable, some of the signaling pathways and several important molecules involved in AD pathogenesis have been identified. The amyloid (Aβ) hypothesis is the most widely accepted molecular explanation. However, recent large-scale clinical phase 3 trials of monoclonal antibodies targeting Aβ have all ended in failure, indicating the complexity and difficulty of treating AD, while clinical research on drugs targeting tau protein is not optimistic, indicating that the road to developing AD drugs is long[3]. Due to the significant difficulties encountered in conventional research and traditional drug treatment, there is an increasing demand for innovative ideas in the development of drugs for treating AD.
Molecular docking can provide useful biological information for the design of new inhibitors, reducing the time needed for chemical synthesis and the cost of biological testing. It also allows simulations of the mechanism of drug action and the prediction of therapeutic doses, as well as the discovery and verification of novel targets and optimization of the pharmacokinetic characteristics of drugs[4]. There have been many animal experiments conducted on the treatment of AD by controlling neuroinflammation, especially in the development of novel drugs targeting the NLRP3 (NOD-like receptor thermal protein domain associated protein 3) inflammasome, but there is still a long way to go in clinical drug trials[5]. The development of nanotechnology provides the possibility of solving some limitations associated with the delivery of active candidate drugs, and has also been used in the development of drugs for AD. In recent years, replacement therapy has attracted significant attention, and traditional Chinese medicine (TCM) or neurotrophic supplements have been demonstrated to be effective in treating AD[6]. The following is a brief analysis of some recent advances in AD drug research.
DRUGS FOR TREATING AD BY BLOCKING ACETYLCHOLINESTERASE
Reduced levels of acetylcholine (ACh) are associated with cognitive impairment and abnormal behavior, and the onset of AD is closely related to a lack of ACh in the brain. Inhibition of acetylcholinesterase (AChE) activity increases the effective amount of ACh, thus reducing the progression of cognitive impairment. The first AChE inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of AD was tacrine, which has subsequently been withdrawn due to its many side effects. At present, donepezil, rivastigmine and galanthamine are AChE inhibitors approved by the FDA that are used to treat AD, with good clinical efficacy. These compounds bind reversibly to AChE, inhibiting its activity and thus increasing ACh levels[7]. Donepezil, a derivative of indone benzyl piperidine, is a long-acting cholinesterase inhibitor with reversible selective deacetylation in the central nervous system. As an AChE inhibitor, donepezil is 10 times more effective than tacrine, and its selectivity for AChE is about 750 times that of butyrylcholinesterase. Donepezil binds to the A chain through Van der Waals forces, π–σ, π–π, and alkyl bonds. In addition, the phenyl nucleus of indacone interacts via π–π bonds with Trp286 in the active center of AChE, inactivating the enzyme. Donepezil has been shown to be effective in improving memory, reducing hallucinations, and enhancing attention[8].
Lismin is a carbamate derivative, which can irreversibly bind to AChE and inactivate it, thus indirectly leading to the increase of ACh concentration. Because of its preferential selectivity to hippocampus and cortex, it shows that it can increase the level of synaptic neurotransmitters and improve the function of cholinergic receptors. The use of lismin patches has a better therapeutic effect[9]. Galanthamine has higher selectivity for AChE. It forms π–alkyl and π–π bonds with the length of 4.7–4.8 with Trp286 on two AChE chains through cyclohexene-2-alcohol and benzene ring, and also binds to the A chain of the enzyme through oxygen atoms and hydrogen bonds of methoxy group. Besides acting on AChE, it also acts through the allosteric regulation of nicotine receptor, which regulates the release of glutamic acid, serotonin and γ-aminobutyric acid, and has a beneficial effect on relieving dementia symptoms[10]. Huperzine A is a reversible cholinesterase inhibitor, which can improve the associative learning, graphic recognition and memory recovery of AD patients. The above Ach inhibitors have been widely used in clinic and achieved different degrees of effect, but these drugs have many side effects, and there is still a big gap in reversing the progress of AD and completely controlling the symptoms of AD.
NMDA RECEPTOR ANTAGONISTS AND SOME NEUROPROTECTIVE AGENTS
Memantine is an antagonist of the N-methyl-D-aspartate glutamate (NMDA) receptor. As early as 2003, some European countries had approved the use of memantine for clinical treatment of AD. Multiple phase 3 clinical trials of metatron treatment for dementia have been completed in other countries and industries around the world; all of which have confirmed its effectiveness in treating AD. Meijingang can inhibit glutamate function and increase dopamine transmission at the same time. Glutamate is an excitatory neurotransmitter that is closely related to the onset of AD, while dopamine is a neurotransmitter that can increase pleasure experiences and improve cognitive function. Meijingang mainly treats dementia by increasing attention and improving episodic memory. For patients with ineffective use of cholinesterase inhibitors, it is recommended to switch to memantine or combine cholinesterase inhibitors with memantine[11].
Sodium oligomannate is an acidic oligosaccharide compound extracted from marine plant brown algae, independently developed by China and approved for clinical use. This drug has shown certain therapeutic effects in treating mild to moderate AD by controlling brain neuroinflammation caused by intestinal microbiota imbalance[12]. Dexmedetomidine (Precedex) is a selective antagonist of 2 adrenergic receptors, which has undergone phase 1 clinical trials for AD treatment, with the final efficacy to be determined. Trehalose is a nonreducing disaccharide and serves as a target for rapamycin kinase complex 1 independent autophagy inducer. It protects neurons by inducing autophagy and clearing Aβ protein aggregates. Recently, clinical trials have used trehalose to treat dementia[13].
Increasing evidence shows that chronic neuroimmune inflammation plays a role in the pathogenesis and progress of AD. Chronic inflammation can lead to the activation of microglia, which can produce cytokines, chemokines and reactive oxygen species, which cause damage to neurons and lead to the development of cognitive symptoms. The activation of inflammatory corpuscles of NLRP3 may play an important role in the pathogenesis of some AD patients. Diacetyl-p-phenylenediamine (DAPPD) has the ability to regulate the function of microglia, inhibit neuroinflammation and alleviate cognitive defects. In the transgenic mouse model of AD, Park et al[14] found that DAPPD can control the occurrence and deterioration of AD by affecting the nuclear factor B1 signal transduction pathway and inhibiting the activation of NLRP3 inflammatory corpuscles. Progesterone (PG) has a unique neuroprotective effect. Some researchers have found that PG can significantly inhibit the activation of NLRP3 inflammatory corpuscles induced by Aβ, suggesting that the neuroprotective mechanism of NLRP3-caspase-1 inflammatory corpuscles regulated by PG may be a potential therapeutic target to improve the pathophysiological process of AD[15]. Stavudine (D4T) is a nucleoside reverse transcriptase inhibitor, which can block the assembly of inflammatory corpuscles of NLRP3. Rosa et al[16] found that D4T can reduce the production of interleukin-18 and caspase-1, reduce the phagocytosis of Aβ, and stimulate Aβ autophagy of macrophages. These effects can be shown by downregulation of extracellular signal-regulated protein kinases 1 and 2 and protein kinase B phosphorylation, showing that D4T can reduce the activation of inflammatory corpuscles of NLRP3.
DRUGS AND ANTIBODIES FOR THE TREATMENT OF AD
The oligomerization of beta Aβ and its interaction with various nerve cells lead to some pathophysiological abnormalities in the brain of AD patients, including mitochondrial dysfunction, tau phosphorylation, activation of immune inflammatory factors, dysregulation of calcium metabolism, and enhanced activity of glycogen synthase kinase 3β (GSK-3β). According to the amyloid cascade theory, the main factor causing AD is the aggregation of Aβ, followed by the formation of senile plaques, which damage nerve cells and brain function. If we want to prevent AD or its development, it is mainly achieved by reducing the production of Aβ, preventing Aβ aggregation, and increasing Aβ clearance[17]. There are two types of vaccine research: (1) Active immunization; and (2) passive immunization. The goal of active immunization is to develop an A42 vaccine that targets the formation of amyloid plaques. The three key enzymes involved in processing amyloid precursor protein have become drug targets for the development and treatment of AD. Drugs such as β-secretase inhibitors, γ-secretase inhibitors and α-secretase promoters have emerged successively. Among this large class of chemical reagents, drugs that have entered clinical trials include elenbecestat, umibecestat, verubecestat, ataabecestat and semagacestat[18].
In addition, immunotherapy can stimulate the immune system to produce autoantibodies or use exogenous antibodies to achieve the above treatment ideas. They are Aβ aggregation inhibitors and some relatively specific monoclonal antibodies. Drugs that have undergone clinical trials include aducanumab, AN-1792, solanezumab, lecanemab, donanemab, ABvac40, etc. AN-1792 is the first Aβ vaccine, but its efficacy in later clinical trials has been unsatisfactory, and ABvac40 is the first active vaccine targeting the C terminus of the Aβ 40 peptide. Anti Aβ 40 antibodies can prevent and treat the production and aggregation of toxic substances of Aβ 40. Although the neurotoxicity of Aβ 40 is lower than that of Aβ 42, this drug is currently undergoing phase 3 clinical trials[19]. Phase 3 clinical trials are the final confirmation of drug safety and efficacy, requiring ~600 or more participants and lasting > 5 years, with at least 80% of patients successful. Aducanumab was approved by the US FDA for clinical use in 2021. It is currently the only monoclonal antibody drug officially approved for the treatment of AD. The drug can cross the blood–brain barrier and bind to amyloid protein, thereby helping to degrade and clear excess Aβ in the brain, which can improve cognitive function in AD patients. However, there is significant debate in the academic community regarding aducanumab, mainly due to its unstable therapeutic efficacy and significant side effects[20]. The above-mentioned drugs that entered large-scale clinical trials in phase 2 or 3 were rarely successful, which led clinical scientists to reflect on whether the presence of Aβ aggregates and tau protein fibers is the main risk of AD in drug research and development, and whether the mainstream neuropsychiatric theory of AD is misleading.
DRUGS AND ANTIBODIES DESIGNED FOR TAU PROTEIN
In the past 10 years, the viewpoint that tau protein causes AD has attracted more attention, and the tau protein superphosphate theory has emerged. When tau is hyperphosphorylated, it can produce neurofibrillary tangles, damage the normal function of neurons, and accelerate their degeneration, leading to AD. Because the correlation between tau pathology and cognitive impairment is stronger than that of Aβ lesions, targeting tau is expected to be more effective than clearing Aβ. In the past, anti-tau protein therapy was mainly based on inhibiting related kinases, or inhibiting tau aggregation, or stabilizing microtubules, but these methods were either too toxic or ineffective, and most of them had stopped. At present, the main direction of targeted therapy of tau protein in clinical trials is immunotherapy, which is said to be effective in many clinical studies[21]. Active immunization against tau protein in the treatment of AD is represented by anti-tau vaccine (AADvac1) and phosphorylated tau (ACI-35). AADvac1 antibody can prevent tau oligomerization, mainly by binding the six amino acid sequence HXPGGG of tau protein to prevent microtubule synthesis. ACI-35 targets the pSer396/404 epitope of tau protein and has been clinically tested in AD patients to evaluate the tolerance and immunogenicity of ACI-35246. At present, the clinical trial drugs targeting tau protein by passive immunization are RG7345, BMS-986168, C2N-8E12, RO 7105705, LY3303560 and INJ-63733657260, etc. These drugs act on different sites of tau protein, for example: (1) RG7345 can recognize tau protein phosphorylated at Ser422 site; and (2) C2N-8E12 can recognize amino acids 25-30 of tau protein. They are all in clinical trials ranging from phase 1 to 3, and the curative effect is uneven[22]. Cyclin-dependent kinase 5, GSK3 and mitogen-activated protein kinase are all key enzymes that control tau protein phosphorylation. At present, there have been some studies on these related signal proteins[23].
The combination of multiple therapies may be more effective in treating AD than using a single drug, because the onset of AD has complex pathophysiological mechanisms and there may be a synergistic relationship between Aβ and tau. In phase 2 clinical trials, the anti-Aβ antibody bapineuzumab can reduce the phosphorylation level of tau protein in the cerebrospinal fluid of AD patients. However, in phase 3 clinical trials, bapineuzumab had no effect on the neuropathology of tau protein. This result suggests that clearing Aβ during active or passive immunity cannot fully reduce tau levels to alter disease progression[24]. Many drug research paths are winding. For example, encouraging results have been achieved in animal studies using methylene blue derivatives, but their clinical research data is not ideal; curcumin, limited by its bioavailability, has not yet been proven to have therapeutic effects on human tau like degeneration; MK-8719 can increase the level of O-GlcNA acylation protein, showing promising application prospects, but its phase 2 clinical trial has not yet reached a definite conclusion[25]. Overall, both active and passive immunization strategies have their own advantages, and the combination of tau and Aβ targeted immunotherapy through antibody engineering may significantly improve efficacy. The cost of drug treatment is also a problem that needs to be seriously considered. We hope that some AD patients in underdeveloped areas can also get effective treatment.
TCM REPLACEMENT THERAPY AND DRUG ADJUVANT THERAPY
Some drugs developed and refined from TCM also play a certain role in the prevention and treatment of AD. Ginkgo biloba extract has the effects of promoting blood circulation, removing blood stasis, dredging channels and activating collaterals. It was originally used to treat vascular dementia, and later it was found to be effective in treating AD. Ginseng has the effects of invigorating qi and blood, calming the nerves and improving intelligence; Astragalus has the effects of enhancing immunity and reducing blood viscosity; Polygonatum sibiricum has the functions of nourishing kidney, replenishing essence, nourishing heart and calming nerves; Gastrodia elata has the function of calming the liver and calming the wind; Lycium barbarum has the function of nourishing liver and kidney, etc. The combination of the above TCMs alone or in combination shows the effect of improving cognitive function. Cannabis plants contain cannabinoids, and cannabinoids contain δ-9-tetrahydrocannabinol and cannabidiol, both of which have anti-inflammatory and neuroprotective effects, and can improve cognitive function and assist in the treatment of AD[26]. In fact, huperzine A is also a natural plant alkaloid extracted from Huperzia serrata, a Chinese patent medicine plant. Later, it was confirmed by western medicine that it has the activity of inhibiting AChE, thus showing the efficacy of treating AD.
The route of administration and drug absorption effect in AD drug therapy are also a research issue worthy of attention. Due to the natural obstacle of the blood–brain barrier, the effect of some drugs for treating AD is reduced or even clinical trials fail. However, nanoparticles are helpful for the delivery of such drugs. Nanoparticles can improve biocompatibility, prolong half-life, transport macromolecules, cross the blood–brain barrier and reach the central nervous system, showing good targeting ability[27]. AD patients are often accompanied by mental disorders, or symptoms such as depression and anxiety. The treatment for these symptoms is important to improve the quality of life of patients, and there are many drugs to choose from. However, these drugs are not the scope of this article. For the treatment of advanced AD patients, drug therapy may be more important than nondrug therapy. There are many combinations of drug therapy and nondrug therapy, and there is no recognized best combination at present. It should be emphasized that any patient advocates comprehensive treatment and makes a special treatment plan for each patient.
CONCLUSION
Due to the complex and numerous factors that affect the onset of AD, it is necessary to comprehensively analyze and identify the goals of control. The establishment of multitarget targeted precision therapy systems is a joint action aimed at key nodes of multiple signaling pathways involved in the pathogenesis of AD. Inhibition of cholinesterase activity, blockade of NMDA receptors, antibody targeting of Aβ and tau proteins, substitution therapy with TCM, and improvement of drug absorption are all current directions for drug treatment of AD[28]. The fact that a single treatment method or drug may not be effective does not mean that this treatment method or drug should be abandoned, but rather that serious improvement or seeking combination therapy is needed. The clinical characteristics and pathophysiology of AD patients are different. Typical randomized controlled trials need to be conducted on a large scale to obtain reliability. Tracking big data can improve the accuracy of measurement results. The development of AD drugs is going through a new stage from natural randomness to more rigorous and efficient[29]. The best treatment for AD is definitely comprehensive therapy, which combines various drugs, cognitive function training, nursing assistance, and community organizations to form the so-called dementia processing unit and is receiving attention[30]. If patients are found to exhibit symptoms related to dementia, it is necessary to seek medical attention in a timely manner, as early diagnosis and reasonable treatment can improve quality of life, among which drug therapy remains the main method for treating AD.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Medicine, research and experimental
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade C
Creativity or Innovation: Grade C
Scientific Significance: Grade C
P-Reviewer: Chakrabarti S S-Editor: Luo ML L-Editor: Kerr C P-Editor: Zhang XD
