The cells of the oligodendrocyte lineage are differentially altered by tau accumulation and amyloidosis

SCA Ferreira
2020
Oligodendrocytes produce and wrap an insulating, fatty substance called myelin around axons to increase the conduction velocity of action potentials along these axons and to provide them with critical metabolic support. Highly myelinated white matter regions are amongst the first to be damaged in Alzheimer's disease (AD), and early oligodendrocyte damage has been detected in transgenic mice carrying human genetic variants associated with the development of AD. In diseases such as multiple
more » ... h as multiple sclerosis, immature brain cells called oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes in an attempt to replace oligodendrocytes lost to the disease, restore action potential conduction speed and protect neurons from further damage. However, OPC fate in the early stages of ADlike pathology is unknown. In this thesis, I have shown that the cells of the oligodendrocyte lineage respond differently to hyperphosphorylated microtubule-associated protein tau (tau) (Chapter 3) and amyloidosis (Chapter 4), two major pathological features of AD, respectively recapitulated in transgenic mice by the overexpression in neurons of a human genetic variant of microtubule-associated protein tau (MAPT) or the amyloid precursor protein (APP). Overexpression of MAPT in neurons indirectly increased new oligodendrocyte addition throughout the brain; however, this was not associated with a change in total oligodendrocyte number, proportion of myelinated axons and myelin thickness in MAPT mice compared to WT (Chapter 3). The OPC response to glutamate and GABA was unchanged in pre-symptomatic MAPT mice; however, OPC responded more robustly to GABA in early amyloid pathology. By overexpressing APP in neurons and oligodendrocytes throughout life, developmental myelin thickness was increased, but amyloid plaque formation was also coincident with an increase in oligodendrogenesis between 5 and 6 months of age in APP mice (Chapter 4). Together, this thesis suggests that oligodendrocyte turnover is an ear [...]
doi:10.25959/100.00034892 fatcat:olbtqd47pbhplchum3lc5gagc4