Alzheimer disease : subcellular Aβ mechanisms and treatment strategies

The amyloid β-peptide (Aβ) is the key molecule in the pathogenesis of Alzheimer disease (AD), but the mechanisms of its toxicity are still largely unknown. This thesis includes studies aimed at studying Aβ induced mechanisms in neurons at the subcellular level and explore effective AD treatment strategies.

In paper I, we detected Aβ oligomerization in endolysosomes of hippocampal neurons by live cell Förster resonance energy transfer (FRET) imaging. In paper II, we investigated the amyloidogenic amyloid precursor protein (APP) processing/Aβ42 production in the endolysosomal pathway in hippocampal neurons by using super-resolution microscopy. In paper III, we visualized Aβ42 uptake in neurons, estimated the accumulation rate and intravesicular concentration of endocytosed Aβ42, and demonstrated Aβ42 induced endolysosomal leakage. In paper IV, we studied neuronal uptake and subcellular distribution of Bri2 BRICHOS protein and used the FRET system established in paper I to evaluate its effectiveness in inhibiting Aβ42 oligomers in hippocampal neurons.

The findings described in this thesis increase the understanding of the role of intracellular Aβ in AD and add details to the amyloid cascade hypothesis. Moreover, this thesis also suggests a potential anti-amyloid treatment strategy.

List of scientific papers

I. Live Cell FRET Imaging Reveals Amyloid β-Peptide Oligomerization in Hippocampal Neurons. Gao Y, Wennmalm S, Winblad B, Schedin-Weiss S, Tjernberg LO. International Journal of Molecular Sciences. 2021;22(9):4530.
https://doi.org/10.3390/ijms22094530

II. A Super-Resolved View of the Alzheimer's Disease-Related Amyloidogenic Pathway in Hippocampal Neurons. Yu Y, Gao Y, Winblad B, Tjernberg LO, Schedin-Weiss S. Journal of Alzheimer's Disease. 2021;83(2):833-852.
https://doi.org/10.3233/JAD-215008

III. Invisible killer: intracellular Aβ accumulation causes endolysosomal leakage in hippocampal neurons. Gao Y, Schedin-Weiss S, Winblad B, Tjernberg LO. [Manuscript]

IV. Bri2 BRICHOS enters neurons and reduces intraneuronal Aβ42 oligomerization. Gao Y, Pelcman J, Kronqvist N, Winblad B, Johansson J, Schedin-Weiss S, Tjernberg LO. [Manuscript]