The incidence of Alzheimer's Disease is increasing each year and is the most common cause of dementia.

A Queen Mary University of London-led team of scientists harnessed induced pluripotent stem cell (iPSC) technology and hairs donated by individuals with Down syndrome (DS), to develop a rapid in vitro cell-based screening system that recapitulates the primary features of Alzheimer’s disease (AD) progression, which they suggest could be used to test potential drug candidates. The team’s studies identified a gene called BACE2 that acts to naturally suppress the signs of AD in human brain cells, and which could feasibly represent a therapeutic target.

Research lead Dean Nižetić, PhD, commented, “This work represents a remarkable achievement, as this is the first cell-based system that has the full trio of Alzheimer’s-pathologies, without any artificial gene overexpression. This system opens up the prospect for screening for new drugs aimed at delaying or even preventing Alzheimer’s before neuronal death starts.”

Nižetić and colleagues reported on their studies in Molecular Psychiatry, in a paper titled, “Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.”

The main challenge in testing Alzheimer’s drugs in clinical trials is that participants need to have symptoms. But once people have symptoms, it is usually too late for treatments to have a significant effect, given the degree of brain cell death. The only current way to evaluate potential preventative strategies is by identifying participants who are at higher risk of developing AD and whether the treatments can help to prevent the onset of AD.

One group of people known to have an increased risk of AD are those with Down’s syndrome, 70% of who will develop dementia during their lifetime. Down’s syndrome results from an extra copy of chromosome 21 (trisomy 21; T21), which carries the gene for β-amyloid-(Aβ)-precursor-protein (APP), so Down’s syndrome patients effectively have an extra copy of this gene. Mutations in or overexpression of APP are linked with the development of Alzheimer’s disease.

To develop their in vitro system, the researchers collected hair cells from people with DS and reprogrammed the cells to become stem cells, which were then triggered to redifferentiate into brain cells. In the brain-like organoids that formed the researchers saw Alzheimer’s-like pathology develop rapidly, including the hallmark trio signs of Alzheimer’s progression—amyloid plaque-like lesions, progressive neuronal death, and abnormal accumulations of a protein called tau inside neurons. “The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss,” the authors wrote. Interestingly, the presence or absence of AD-like pathology was donor-specific, and reproducible for individual organoids and iPSC lines.

The researchers showed that their in vitro system could be used for early testing of potential preventive drugs. They took two different drugs that are known to inhibit β-amyloid production, tested them on these brain cells, and in six weeks showed that the drugs prevented the onset of Alzheimer’s-pathology. Although the two compounds that they used to test the system failed clinical trials for other reasons and aren’t suitable treatments for Alzheimer’s, the team demonstrated proof-of-principle that the system could be used on any drug compound, and within six weeks show whether or not a compound has potential for further investigation.

The team’s studies with the iPSC-derived organoid system also uncovered proof of the existence of a naturally functioning Alzheimer’s suppressor gene, BACE2. “At least three different activities of BACE2 were recorded with regards to APP processing,” they wrote, “as an auxiliary β -secretase (pro-amyloidogenic), as a θ–secretase (degrading the β-CTF and preventing the formation of Aβ), and as Aβ-degrading protease (AβDP).” Results using their system showed that “pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β- and γ-secretase inhibition.”

The researchers’ results indicated that BACE2 acts in a similar way to tumor suppressor genes in cancer, with increased activity of the gene contributing to the prevention/slowing down of Alzheimer’s in human brain tissue. “We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialed BACE1 inhibitors,” they commented.

One of the functions of BACE2 is thus as an Aβ-degrading protease (AβDP), and the investigators’ results also suggested that BACE1 inhibitors that have been tested against AD may act to block this beneficial actions of BACE2, which may help to explain why some BACE1 inhibitors have failed in human testing. “We demonstrated that at least two BACE1 inhibitor compounds (of which one was recently used in clinical trials) inhibit the AβDP (Aβ-clearance) activity of BACE2 in a dose-dependent manner,” they stated. “This has, to our knowledge, so far not been shown, and could provide an additional explanation for the failure of some BACE1 inhibitor clinical trials, and should be taken into consideration when testing new inhibitors.”

The authors suggested that BACE2 could in the future be used as a biomarker to determine people’s risk of developing AD, or as a new therapeutic strategy. “We … show that cerebral organoids from genome-unedited iPSCs could be explored as a system for pre-morbid detection of high-risk population for AD, as well as for identification of natural dose-sensitive AD suppressor genes.”

Nižetić further commented, “Although it’s still early days, the system raises a theoretical possibility for further development as a tool to predict who might develop Alzheimer’s. The same stem cell process could be used on anyone’s hair follicles, the resulting brain cells of which may or may not then develop Alzheimer’s-pathology in the dish. The idea would be to catch the people at higher risk of early disease in a cell-based system, before it starts in a person’s brain, and allow for the possibilities of individualized preventive interventions. We are still a long way from reaching this goal.”

Co-author John Hardy, PhD, from University College London, added, “I think we have the potential now to develop a new, human model of the disease which would be a great step forward.” As the authors concluded, “… our combined data suggest that increasing the action of BACE2 could be exploited as a therapeutic/protective strategy to delay the onset of AD, whereas cross inhibition of BACE2-Aβ DP activity by BACE1 inhibitors would have the unwanted worsening effects on disease progression.”

The discoveries in this study were dependent on contributions from people with DS who kindly accepted to participate in this study, the results of which could be beneficial for people with and without DS in preventing Alzheimer’s. The Down’s Syndrome Association (U.K.) provided essential support and help with recruitment of the participants in the study. Carol Boys, chief executive of the Down’s Syndrome Association, said: “These are exciting results from an extremely eminent group of researchers and another small step towards a possible intervention and treatment for AD. The Down’s Syndrome Association is delighted to have been able to support this brilliant work.”


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