Induced pluripotent stem cells derived from patients with familial Alzheimer's disease and other dementias as novel cell models for neurodegeneration

 Late onset familial alzheimer's disease / Posted 2 years ago

late onset familial alzheimers disease/ Alzheimer disease type 2

Dementia is one of the major health issues facing medicine today, with an increasing number of patients due to a steadily ageing population. Much of what we know about the molecular basis of the various forms of dementia is due to studying rare inherited forms, caused by abnormalities (mutations) in the genes coding for several proteins, including the amyloid precursor protein, Presenilin 1 and 2, progranulin and tau. A major research issue when studying these disorders has been the lack of a valid cell model faithfully replicating the human disease. Recent advances in stem cell technology provide a method with which to develop novel, patientderived cell models for neuronal dysfunction in the dementias. We can take skin biopsies (fibroblasts) from patients who carry dementiacausing mutations and use a combination of factors to cause them to become stem cells. These induced pluripotent stem cells (iPS cells) can then be differentiated into neuronal cells, and because they will contain the patients abnormal protein, we can study how dementiacausing mutations lead to neuronal dysfunction in these cells. Our hypothesis is that the presence of mutations in APP, Tau, GRN, PS1 and PS2 will lead to alterations in gene expression and protein behaviour within these cells, which we will be able to study using a range of genetic, cellular and biochemical techniques. These results will then be compared to data from cells derived from sporadic disease patients and unaffected, agematched controls (as well as mutation carrying fibroblasts and lymphoblasts to study why these mutations only affect neuronal cells), highlighting pathways and processes altered in the disease state, which can then be targeted for therapeutic treatment.

  • Inclusion Criteria :
    • Familial dementia mutation carrying patients. Individuals carrying mutations previously shown to cosegregate with dementia will be recruited.
    • Sporadic dementia controls will be recruited based upon the absence of any mutations in known dementia disease loci and any family history of dementia.
    • Healthy aged matched controls will be included in the study dependent upon no cognitive complaints and no history of neurological illness. Where possible, aged matched controls will include unaffected siblings of mutation carriers.
  • Study start date : 08/03/2010
  • Study end date : 31/03/2022
  • Wales-Based Study Contact : Please speak to your clinician
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