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Title: The contribution of amyloid vs. Tau to Alzheimer's-like phenotypes in transgenic mouse models
Author: Yeap, Jie
ISNI:       0000 0004 7967 690X
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2019
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Both β-amyloid (Aβ) plaques and neurofibrillary Tau tangles are pathological hallmarks of late stage Alzheimer's disease (AD) but their individual contribution to disease onset and progression remains largely unclear. It is now widely agreed that smaller, soluble aggregates of Aβ and Tau confer most of the neurotoxicity and are likely responsible for the disease manifestation. Therefore, there is a requirement for models of dementia with a defined, slow prodromal phase and subtle pathology, which is the desired time point for early diagnosis and therapeutic intervention. While cognitive decline may correlate with soluble Aβ levels in humans, electroencephalography (EEG) studies revealed altered brain electricity activity in asymptomatic carriers of AD risk mutation, suggesting the sensitivity of this technique. This study focused on capturing early AD-related phenotypes in novel transgenic knock-in PLB mouse lines, while segregating the respective contribution of Aβ and Tau pathology. PLB mouse lines express risk genes responsible for Aβ and/or Tau pathology, namely APP (Swe/Lon) or Tau (P301L + R406W), either individually or in combination. Mice underwent a behavioural test battery, for some cohorts combined with EEG, after which brains were harvested for ex vivo studies. Cognitive and EEG changes were detected in all PLB lines compared with wild-type controls. APP mutations contributed to recognition memory deficits, accompanied by EEG Gamma power alterations, and premature ageing of the blood-brain-barrier. Meanwhile, Tau mutations led to early spatial working memory and social deficits, accompanied by Theta frequency alterations, and elevated levels of inflammatory markers. Both APP- and Tau specific early EEG alterations were detected in the double transgenic mice and could be easily segregated, which was not possible by solely assessing their cognitive and molecular profiles. This indicates that EEG-based differential diagnoses may offer greater sensitivity and specificity than cognitive assessments and other biomarkers.
Supervisor: Platt, Bettina ; Riedel, Gernot Sponsor: Alzheimer's Society
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Alzheimer's disease ; Amyloid beta-protein ; Neurofibrils ; Phenotype ; Biochemical markers