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Alzheimer's disease (AD), a disease that is both familiar and unfamiliar, until now, researchers are constantly discovering new disease mechanisms and looking for effective treatments
.
So we can't help asking, where is the next step in AD treatment? Recently, a new paper published in Nature Aging magazine[1] may answer this question to some extent
.
The team of researcher Huang Yadong from the Gladstone Institute found that a powerful fast-acting diuretic, bumetanide, which has been on the market for more than 30 years, successfully reversed AD-related transcriptome characteristics in mouse and human neurons in experiments, and AD-related manifestations.
In addition, through the analysis of the electronic medical records of two independent institutions, they found that the use of bumetanide is associated with a significant reduction in the prevalence of AD in the elderly over 65 years old by 35%-75%! To have such a discovery, we must also talk about 2017, because the development of new AD drugs is a very long process and very expensive.
In order to provide patients with effective treatment faster, researcher Huang Yadong promoted the establishment of the Gladstone Transformation Promotion Center , I hope to find some new use value for the drugs that the FDA has approved for marketing [2]
.
AD patients have significant heterogeneity in genetics, pathology, and clinical manifestations.
It is impossible to develop a drug to cover all patients.
This also brings great challenges to clinical trials of new drugs
.
Researcher Huang decided to start with genes.
His team first analyzed the only publicly available human temporal lobe transcriptome database, which contains AD patients and non-AD control populations and their APOE genotype information
.
APOE gene is the main genetic risk factor for AD.
Compared with APOE3 homozygotes (APOE3/APOE3), APOE4 heterozygotes (APOE3/APOE4) and APOE4 homozygotes (APOE4/APOE4) will increase the risk of AD by 3-4 times and 12, respectively.
-14 times [3-5]
.
According to the APOE genotype and the gender of the patients, the researchers stratified the patients in the database and evaluated their differentially expressed genes
.
In patients with APOE3/APOE3, APOE3/APOE4, and APOE4/APOE4 genotypes, compared with the matched control group, there were 539, 259, and 1079 differentially expressed genes, but only 108 (5.
6%) of them were in the third group.
"Shared" among the group of AD patients
.
Differentially expressed genes also correspond to different signaling pathways, and the three groups of AD patients "shared" 7 of them
.
This confirms the genetic heterogeneity of AD patients
.
AD patients’ APOE genome-specific expression increases (e) and decreases (f) genes, as well as differentiated signaling pathways (g).
Next, they referred to the ideas of cancer drug reuse research, hoping to find a way to integrate the patient’s transcriptome A drug that has a characteristic "twisting" back to a normal state
.
Based on the calculated "reversal scores" of different drugs, the researchers selected the 5 highest-scoring candidates as candidates, searched for their pharmacological information and potential mechanisms of action, and finally bumetanide stood out
.
Next is the time to verify the effect of bumetanide! The researchers chose two mouse models
.
The first is APOE4-KI mice, which usually develop learning and memory deficits around 15 months (equivalent to 60-year-old humans)
.
After treatment with bumetanide, the abnormally expressed genes in the brains of elderly APOE4-KI mice were reversed, initially showing the potential of bumetanide
.
The neurons in the hippocampal CA area of the aged APOE4-KI mice showed hyperexcitability, which is a known AD-related neuron phenotype.
After 8 weeks of bumetanide treatment, this pathological manifestation was reversed
.
Similarly, the plasticity of neurons is almost completely restored
.
Changes in the excitability (a) and plasticity (b) of neurons in the hippocampal CA area of aged APOE4-KI mice, APOE4/APOE4 mice received bumetanide treatment (blue) and recovered to a level similar to APOE3/APOE3 mice These changes are reflected in the improvement of cognitive deficits in mice
.
Before treatment, 22-month-old female APOE4-KI mice were very confused in the Morris water maze.
The time required to find a hidden platform was always longer than that of APOE3-KI mice, indicating that their spatial memory ability was impaired, but after treatment , It can reach a level similar to that of APOE3-KI mice
.
Of course, the researchers ruled out the possibility that bumetanide achieved this effect by increasing the swimming speed of mice or improving the learning ability
.
Among the several main neuron types in the hippocampus of mice, the researchers observed that 135 signaling pathways were enriched in at least one of them.
These neurons showed significant transcriptome characteristic "torsion", and these signaling pathways There are 28 overlaps with human APOE4/APOE4 AD patients
.
The ageing transcriptome characteristics of the brain mediated by APOE4 were also reversed after bumetanide treatment
.
The second mouse model selected by the researchers is the J20/E4-KI mouse, which carries the APP mutation associated with early-onset familial AD, and it will produce obvious Aβ plaques from about 6 months of age.
.
They treated the mice with bumetanide at the age of 10 months for 12 weeks
.
The treatment also restored the normal neuronal excitability and plasticity of J20/E4-KI mice, and also significantly reduced Aβ plaques
.
J20/E4-KI mouse control group (d) and Aβ plaque immunostaining results after receiving bumetanide treatment (e).
In addition to the mouse model, the researchers also showed that the APOE4/APOE4 phenotype was induced by humans.
Experiments were performed on human neurons derived from stem cells (iPSC)
.
The AD-related transcriptome characteristics of neurons treated with bumetanide were smoothly "twisted"
.
If bumetanide is really so effective, as an old drug that has been on the market for more than 30 years, there must be some differences in the incidence of AD in the patient population using him and other populations
.
To verify this, the researchers analyzed two independent large electronic health record databases, one from the University of California, San Francisco, containing information on 1.
3 million patients visited from 2012 to 2019, and the other from the Mount Sinai Health System, covering 3.
9 million patients
.
There are 1850 and 1901 bumetanide users in the two databases each over the age of 65
.
Because bumetanide is used in the treatment of some hypertensive patients, and hypertension is a known risk factor for AD [6], the researchers matched 10 control cohorts, and the number of people in each cohort was bumetanide Twice the number of patients, using a propensity scoring method based on age, race, gender, hypertension, and edema diagnosis
.
According to calculations, the prevalence of AD among people treated with bumetanide is reduced by 35%-75%
.
Researcher Huang Yadong said that since the two electronic health record databases did not record the APOE genotypes and stratification of patients, this real-world data suggests that bumetanide may be able to combat AD more broadly, not limited to APOE4/APOE4 AD patients
.
Based on these findings, they are planning to cooperate with multiple medical centers to carry out clinical trials of bumetanide in the treatment of AD patients with APOE4
.
But the researchers said that doctors should not prescribe bumetanide for AD patients until clinical trials have confirmed its efficacy
.
Reference materials: [1] https:// https://gladstone.
org/news/can-already-approved-drug-treat-alzheimers- disease[3] Huang Y, Mucke L.
Alzheimer mechanisms and therapeutic strategies[J].
Cell, 2012, 148(6): 1204-1222.
[4] Liu CC, Kanekiyo T, Xu H, et al.
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy[J].
Nature Reviews Neurology, 2013, 9(2): 106-118.
[5] Corder EH, Saunders AM, Strittmatter WJ, et al.
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families[J].
Science, 1993, 261(5123): 921-923.
[6] Lennon MJ, Makkar SR, Crawford JD, et al.
Midlife hypertension and Alzheimer's disease: a systematic review and meta-analysis[J].
Journal of Alzheimer's Disease, 2019, 71(1): 307-316.
.
So we can't help asking, where is the next step in AD treatment? Recently, a new paper published in Nature Aging magazine[1] may answer this question to some extent
.
The team of researcher Huang Yadong from the Gladstone Institute found that a powerful fast-acting diuretic, bumetanide, which has been on the market for more than 30 years, successfully reversed AD-related transcriptome characteristics in mouse and human neurons in experiments, and AD-related manifestations.
In addition, through the analysis of the electronic medical records of two independent institutions, they found that the use of bumetanide is associated with a significant reduction in the prevalence of AD in the elderly over 65 years old by 35%-75%! To have such a discovery, we must also talk about 2017, because the development of new AD drugs is a very long process and very expensive.
In order to provide patients with effective treatment faster, researcher Huang Yadong promoted the establishment of the Gladstone Transformation Promotion Center , I hope to find some new use value for the drugs that the FDA has approved for marketing [2]
.
AD patients have significant heterogeneity in genetics, pathology, and clinical manifestations.
It is impossible to develop a drug to cover all patients.
This also brings great challenges to clinical trials of new drugs
.
Researcher Huang decided to start with genes.
His team first analyzed the only publicly available human temporal lobe transcriptome database, which contains AD patients and non-AD control populations and their APOE genotype information
.
APOE gene is the main genetic risk factor for AD.
Compared with APOE3 homozygotes (APOE3/APOE3), APOE4 heterozygotes (APOE3/APOE4) and APOE4 homozygotes (APOE4/APOE4) will increase the risk of AD by 3-4 times and 12, respectively.
-14 times [3-5]
.
According to the APOE genotype and the gender of the patients, the researchers stratified the patients in the database and evaluated their differentially expressed genes
.
In patients with APOE3/APOE3, APOE3/APOE4, and APOE4/APOE4 genotypes, compared with the matched control group, there were 539, 259, and 1079 differentially expressed genes, but only 108 (5.
6%) of them were in the third group.
"Shared" among the group of AD patients
.
Differentially expressed genes also correspond to different signaling pathways, and the three groups of AD patients "shared" 7 of them
.
This confirms the genetic heterogeneity of AD patients
.
AD patients’ APOE genome-specific expression increases (e) and decreases (f) genes, as well as differentiated signaling pathways (g).
Next, they referred to the ideas of cancer drug reuse research, hoping to find a way to integrate the patient’s transcriptome A drug that has a characteristic "twisting" back to a normal state
.
Based on the calculated "reversal scores" of different drugs, the researchers selected the 5 highest-scoring candidates as candidates, searched for their pharmacological information and potential mechanisms of action, and finally bumetanide stood out
.
Next is the time to verify the effect of bumetanide! The researchers chose two mouse models
.
The first is APOE4-KI mice, which usually develop learning and memory deficits around 15 months (equivalent to 60-year-old humans)
.
After treatment with bumetanide, the abnormally expressed genes in the brains of elderly APOE4-KI mice were reversed, initially showing the potential of bumetanide
.
The neurons in the hippocampal CA area of the aged APOE4-KI mice showed hyperexcitability, which is a known AD-related neuron phenotype.
After 8 weeks of bumetanide treatment, this pathological manifestation was reversed
.
Similarly, the plasticity of neurons is almost completely restored
.
Changes in the excitability (a) and plasticity (b) of neurons in the hippocampal CA area of aged APOE4-KI mice, APOE4/APOE4 mice received bumetanide treatment (blue) and recovered to a level similar to APOE3/APOE3 mice These changes are reflected in the improvement of cognitive deficits in mice
.
Before treatment, 22-month-old female APOE4-KI mice were very confused in the Morris water maze.
The time required to find a hidden platform was always longer than that of APOE3-KI mice, indicating that their spatial memory ability was impaired, but after treatment , It can reach a level similar to that of APOE3-KI mice
.
Of course, the researchers ruled out the possibility that bumetanide achieved this effect by increasing the swimming speed of mice or improving the learning ability
.
Among the several main neuron types in the hippocampus of mice, the researchers observed that 135 signaling pathways were enriched in at least one of them.
These neurons showed significant transcriptome characteristic "torsion", and these signaling pathways There are 28 overlaps with human APOE4/APOE4 AD patients
.
The ageing transcriptome characteristics of the brain mediated by APOE4 were also reversed after bumetanide treatment
.
The second mouse model selected by the researchers is the J20/E4-KI mouse, which carries the APP mutation associated with early-onset familial AD, and it will produce obvious Aβ plaques from about 6 months of age.
.
They treated the mice with bumetanide at the age of 10 months for 12 weeks
.
The treatment also restored the normal neuronal excitability and plasticity of J20/E4-KI mice, and also significantly reduced Aβ plaques
.
J20/E4-KI mouse control group (d) and Aβ plaque immunostaining results after receiving bumetanide treatment (e).
In addition to the mouse model, the researchers also showed that the APOE4/APOE4 phenotype was induced by humans.
Experiments were performed on human neurons derived from stem cells (iPSC)
.
The AD-related transcriptome characteristics of neurons treated with bumetanide were smoothly "twisted"
.
If bumetanide is really so effective, as an old drug that has been on the market for more than 30 years, there must be some differences in the incidence of AD in the patient population using him and other populations
.
To verify this, the researchers analyzed two independent large electronic health record databases, one from the University of California, San Francisco, containing information on 1.
3 million patients visited from 2012 to 2019, and the other from the Mount Sinai Health System, covering 3.
9 million patients
.
There are 1850 and 1901 bumetanide users in the two databases each over the age of 65
.
Because bumetanide is used in the treatment of some hypertensive patients, and hypertension is a known risk factor for AD [6], the researchers matched 10 control cohorts, and the number of people in each cohort was bumetanide Twice the number of patients, using a propensity scoring method based on age, race, gender, hypertension, and edema diagnosis
.
According to calculations, the prevalence of AD among people treated with bumetanide is reduced by 35%-75%
.
Researcher Huang Yadong said that since the two electronic health record databases did not record the APOE genotypes and stratification of patients, this real-world data suggests that bumetanide may be able to combat AD more broadly, not limited to APOE4/APOE4 AD patients
.
Based on these findings, they are planning to cooperate with multiple medical centers to carry out clinical trials of bumetanide in the treatment of AD patients with APOE4
.
But the researchers said that doctors should not prescribe bumetanide for AD patients until clinical trials have confirmed its efficacy
.
Reference materials: [1] https:// https://gladstone.
org/news/can-already-approved-drug-treat-alzheimers- disease[3] Huang Y, Mucke L.
Alzheimer mechanisms and therapeutic strategies[J].
Cell, 2012, 148(6): 1204-1222.
[4] Liu CC, Kanekiyo T, Xu H, et al.
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy[J].
Nature Reviews Neurology, 2013, 9(2): 106-118.
[5] Corder EH, Saunders AM, Strittmatter WJ, et al.
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families[J].
Science, 1993, 261(5123): 921-923.
[6] Lennon MJ, Makkar SR, Crawford JD, et al.
Midlife hypertension and Alzheimer's disease: a systematic review and meta-analysis[J].
Journal of Alzheimer's Disease, 2019, 71(1): 307-316.
