Age dependent Beta-Amyloid isoforms and implications of different drug treatments as studied in different transgenic mouse models and cell lines

The Amyloid-β (Aβ) peptide is the main component of the the amyloid plaques in Alzheimer’s Disease (AD) and has been implicated to be the cause of the disease. During the last decade it has become increasingly evident that soluble, oligomeric forms of Aβ are more toxic to neurons than the plaques and might play an important role in the disease pathogenesis. The aim of this thesis was to investigate the time course of different Aβ isoforms and species and how these forms affects the neuro-pathological changes seen in AD and how different cholinergic drugs can modulate Aβ and it’s processing. A translational approach ranging from transfected human neuroblas-toma SH-SY5Y/APPswe cells, APPswe and hAChE-Tg//APPswe transgenic mouse models of AD to postmortem AD brain tissue were used to study how changes of different levels of Aβ influence the brain and related processes. APPswe transgenic mice showed already at 7-days of age, high levels of soluble form of Aβ, as a sign for that Aβ starts to aggregate from birth. Be-tween 7 to 90-days of age, the major Aβ isoforms in brain were shorter forms than Aβ1-40. The levels of Aβ1-40 were high and remained fairly constant up to 15- months of age while Aβ1-42 showed an age-dependent consistent increase from 7- days up to 15-months of age. High levels of Aβ oligomers but low levels of synaphtophysin were observed in 90-days-old APPswe mice probably due to the toxicity of the oligomers. Low levels of α7 neuronal nicotinic acetylcholine recep-tors (nAChRs) compared to non-transgenic mice were measured in 7-days-old APPswe mice; while an increased number N-methyl-D-aspartate (NMDA) recep-tors binding sites were found at 21-days of age probably reflecting compensatory mechanisms in response to a high Aβ burden. Epigenetic studies showed increased levels of acetylated (AcH3), and di-methylated (2MeH3) histone H3 at 4-months-old APPswe mice. When a γ-secretase inhibitor reduced Aβ, there was a reduction in AcH3 in SH-SY5Y/ APPswe cells. nAChR agonists showed to influence the Aβ levels in hAChE-Tg//APPswe transgenic mice and in SH-SY5Y/ APPswe cells