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New Brain Model Provides Patient-Specific Alzheimer’s Insights and Predictions of Cognitive Decline

분류 국외뉴스 > R&D성과 등록일 2021-09-02
출처 neurosciencenews 조회 63
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내용바로가기 https://neurosciencenews.com/cognitive-decline-alzheimers-brain-model-19234/
 
New Brain Model Provides Patient-Specific Alzheimer’s Insights and Predictions of Cognitive Decline
  
The team generated induced pluripotent stem cell (iPSC) lines from over 50 different individuals for whom longitudinal clinical data, quantitative neuropathology data, and rich genetic and molecular profiling of brain tissue was also available. The team demonstrated the power of this new resource through a series of studies that turned these human stem cells into brain cells and then analyzed molecular pathways active in these living neurons in a dish.
 
The team identified specific forms of amyloid beta-protein (Aβ) and tau protein associated with cognitive decline and AD, and uncovered signaling pathways influencing the production of these toxic species.
 
Their findings are published in Neuron.
 
“We are finding that different genetic backgrounds in humans generate different profiles of Aβ and tau” said Tracy Young-Pearse, PhD, of the Brigham’s Division of Neurology.
 
“Those stem cell derived neuronal profiles have a predictive nature, in terms of the clinical outcome of an individual’s Alzheimer’s disease. This large set of human cell lines from AD and cognitively normal people provide the scientific community with a powerful experimental system for untangling why some people develop AD and others do not.”
 
The study leveraged a large cross-institutional collaborative effort that follows a cohort of people from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP) at Rush University. All individuals entered the ROS and MAP studies with no history of AD or any other neurological diagnosis, but over one third of them went on to develop AD over time.
 
Stem cell lines were generated from blood samples of over 50 of these individuals, who lived to an average of 90 years of age. While the subjects were alive, detailed clinical records and full genome sequencing were collected for each person. After death, the brains of the deceased also were studied and compared to their cultured brain cells in a dish.
 
The researchers measured Aβ and tau generated by the stem cell-derived neurons and found that specific Aβ and tau species were associated with the levels of plaque and tangle deposition in the brain and the trajectory of cognitive decline.
 
“If you look across cell culture samples from 50 people, you can predict from the Aβ and tau profiles some features of the cognitive status of that person: their rate of cognitive decline and whether they developed AD, which is absolutely remarkable,” Young-Pearse said.
 
The authors recognize that, since participants of the ROS and MAP cohorts were primarily Caucasians of European origin, their observations may not be applicable to more diverse populations. The research team has already undertaken the development of 50 new iPSC lines which will be derived from people of color and non-Caucasian groups.
 
“This is a resource for the whole community, for scientists around the world to use,” said Young-Pearse. “We already have around 50 labs, all around the world, starting to use these cells in their studies.”
 
The research team is also exploring if the stem cell-derived neurons can be used to predict whether drugs like aducanumab, a new Alzheimer’s drug recently approved by the Food and Drug Administration, will be more effective in specific groups of AD patients.
 
“The new Alzheimer’s drug is an antibody that recognizes Aβ and clears it from the brain. Our work shows that different genetic backgrounds of human neurons produce different profiles of Aβ,” said Young-Pearse.
 
Highlights
•Generation and characterization of iPSC lines from 53 deeply phenotyped aged humans
•Degree of congruence in expression profiles between iNs and brain of the same person
•Association of cognitive decline and measures of Aβ and tau in iPSC-derived neurons
•Identification and validation of PP1 as a molecular link between LOAD PRS, Aβ, and tau
 
Summary
 
We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer’s disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology.
 
The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aβ and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain.
 
The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD.