Alzheimer's disease: current treatment and future challenges

Release date: 2014-06-13

It's hard to believe that 40 years ago, we also thought that Alzheimer's disease (AD) was caused by aluminum in the brain. Some people even threw their own pots out of fear of this difficult disease. At present, the hypothesis that aluminum causes AD has not been believed by many people, and at the same time, relevant research is also making great strides: in 1984, researchers found β-amyloid (Aβ) in the brain of AD patients; 1986 In the year, hyperphosphorylated Tau protein has not escaped the eyes of scientists. These are true AD markers and a potential culprit for neuronal death and memory impairment.

Amyloid precursor protein (APP) is a raw material for the manufacture of Aβ. In 1987, the researchers found that the APP gene was located on chromosome 21 and the other risk gene APOE4 was also identified in 1993. In the late 1990s, it was discovered that β-secretase (BACE1) and γ-secretase are responsible for pruning APP, which is the process that leads to the production of Aβ and the death of brain cells. With the birth of new targets, the treatment of AD has gradually become a clue.

In the trenches, the struggle with AD continues. The question at hand is, what is the position we are in this war? Are we going to finish, or are we just getting started? Three experts in the field of AD have discussed this important issue. They are Dr. Murali Doraiswamy from Duke University Hospital, Dr. James Lah from Emory University, and Dagmar Ringe from Brandeis University.

Current AD treatment

Doraiswamy and colleagues point out that we have been able to treat brain neurotransmitters affected by AD, such as elevated acetylcholine levels (galantamine, lismin and donepezil) or block glutamate (Memantine). These drugs can delay the progression of the disease to some extent, but it is undeniable that AD is still in progress. Dr. Doraiswamy said: "At present, the FDA has approved four drugs that alleviate the symptoms of AD. These drugs have moderate efficacy in cognitive decline. Some of these drugs can also be combined, and the effect may be better than monotherapy. Some people It is believed that these drugs can also reduce the time required for the care of the patient and delay the time to enter the nursing home."

"We have a good news and a bad news: the good news is that many of these drugs are not protected by patents, and the price is no longer as high as it used to be; the bad news is that the FDA has not approved more than a decade. New treatments."

Dr. Lah agreed, saying that “the current treatment options are overly restrictive and can be used with some old drugs that have moderate effects on symptoms.”

All three doctors believe that early treatment of AD is very important, and should even intervene as much as possible before the disease progresses. At present, many of the goals of AD treatment are here.

Dr. Ringe pointed out: "In fact, there is no means to cure AD, and we don't know if there will be any in the future. We are not looking for treatment for advanced AD. What we are looking for is treatment for potential AD patients. ”

Doraiswamy agrees with Dr. Ringe's point of view and states: "All trials against AD have failed. However, in the field of 'Which approaches don't work', we have accumulated a lot of lessons; at the same time, we are determining high-risk patients and brain changes. In terms of the timeline, we have also made great progress. Compared with a decade ago, we have a better understanding of which chemical pathways in the brain have problems. We need to speed up the progress before the AD course is fully operational. Provide a stage for the drug to be effective."

Aβ vaccine

Many clinical trials for AD have gone wrong, starting with the Aβ vaccine. The mouse AD model showed that the learning ability and memory of the mice improved after the injection of the Aβ vaccine, and the level of Aβ in the brain did decrease. However, due to safety concerns, the human Aβ vaccine was stopped.

Lah pointed out: "As far as we know, the most serious side effect of Aβ vaccine is cerebral edema. The reason for the termination of the trial in 2000 is that it is hard to blame."

Despite these safety issues, the development of Aβ vaccines continues to advance with rigorous safety monitoring. For example, UB-311 passed a phase of clinical trials and United Biomedical is developing it as a vaccine. Initial studies showed that the cognitive function of a small group of patients with mild AD was improved after using the drug. CAD106 is an anti-Aβ vaccine developed by Merck and Cytos. An early study showed that the vaccine was safe and produced antibodies at the same time, but more trials are needed to prove its effectiveness.

Lah explored other anti-amyloid treatment strategies, with particular reference to monoclonal antibodies. These drugs are administered intravenously and administered once a few weeks. For example, the bapineuzumab developed by Pfizer and Johnson & Johnson did not reach the primary end point of clinical trials, and further research and development was terminated. Lilly's Solanezumab also encountered Waterloo in Phase 3 clinical trials, however, Lah also explained that the drug showed greater potential in post hoc analysis and may be demonstrated in some clinical trials for patients with earlier AD. Benefit from. Therefore, a preventive trial is being conducted on the drug, based on genetic markers and brain imaging, which will identify potential susceptible populations for the drug's efficacy. He is optimistic about Aβ antibodies on the grounds that “if they are used earlier, these drugs may have a role in regulating the disease.”

In addition to the Aβ vaccine, there are some treatments targeting other targets, including γ-secretase and BACE1. As mentioned above, the above two enzymes can produce and release Aβ. To date, none of the clinical trials for the former have been successful: in human trials, γ-secretase inhibitors do not appear to reduce Aβ levels. This condition may be related to the inability of these drugs to stably enter the brain through the bloodstream.

However, BACE1 inhibitors are still promising. In Phase 2/3 clinical trials, Merck developed MK-8931 to meet safety requirements, and the study included mild to moderate AD patients. Merck has continued to work on a Phase 3 APECS trial that will test the efficacy of MK-8931 in patients with early AD. However, BACE1 not only affects Aβ, but also has certain effects on other targets, which may lead to side effects and safety problems, which also raises some concerns. However, the MK-8931's move to Phase 3 clinical trials is a success in itself.

Beta inhibitor

Tau protein hyperphosphorylation is another target for AD treatment. Dr. Lah pointed out: "Pre-clinical work has shown that this route may be equally effective." In the pre-clinical trial, the anti-Tau drug Epothilone B appears to reduce mouse neuronal death, AD. Molecular effects and cognitive problems. This new microtubule stabilizer prevents the destabilization of neuronal microtubules, which is one of the effects of Tau protein hyperphosphorylation. The drug is currently in Phase 1 clinical trials. Other members of the epothilone family are also in the study.

Increased neurotrophic factor

Another potential treatment for AD is directed to neurotrophic factor (NGF), which protects brain cells. CERE-110 is a surgically implanted non-infectious viral system that injects NGF DNA into the brain in an effort to increase NGF production. Through surgery, CERE-110 is implanted into the nucleus of Meynerti, which produces acetylcholine, a degenerative change in this brain region of AD patients. Phase 1 clinical trials showed that CERE-110 was well tolerated. This treatment is undergoing Phase 2 clinical trials. The trial included approximately 50 AD patients, half of whom received CERE-110 and the other half underwent sham surgery, and the results are expected to be released in 2015.

Other treatments

Dr. Doraiswamy introduced other treatments: "Some new treatments are being developed, such as nicotine transmitter regulation therapy, induced stem cell therapy, RNA interference therapy, brain stimulation therapy (direct current stimulation, deep brain stimulation), and metabolic-based therapies. The researchers also explored the role of aerobic exercise and diet therapy. For example, the Exercise and Nutritional L Interventions for coGnitive and cardiovascular Heal Th ENhancement is aimed at the efficacy of these interventions in patients with mild cognitive impairment.

Retromer: What are the new targets for AD?

Recently, Nature Chemical Biology published an inspiring study that explored drugs that affect the retromer complex. Retromer can move proteins, including APP, from endosomes to Golgi for further processing. Proteins associated with retromer allow APP and BACE1 to remain in endosomes, BACE1 cleaves APP, leading to the formation of Aβ, and blocking this process reduces Aβ production. By raising the level of retromer and promoting normal transport, we are expected to prevent AD.

The researchers tested compound R55 in artificially cultured neurons. The results showed that the level of retromer increased and Aβ decreased. Next, the researchers will test the clinical efficacy of R55 in mice.

Ringe is one of the authors of the study. She feels that R55 may represent a class of treatments with less side effects: "We have not tried to over-adjust or lower a certain level... We just return the body to its normal physiological state and return the cells to the right track." The research is still in its early stages, and in the war with AD, retromer is expected to add new ammunition to us.

In 2011, Obama signed the National Alzheimer's Project Act (NAPA) to develop effective therapies for AD by 2025. It seems that the war will continue, but the strategy seems to have a panoramic view.

Source: Medical Pulse

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