Alzheimer’s disease (AD), the most common neurodegenerative disorder, afflicts more than 5 million people in the United States and is characterized by neurofibrillary tangles and the accumulation of β- amyloid (Aβ) plaques in the brain.

A key contributor to the production of Aβ is the protein Presenilin 1 (PS1), a subunit of the γ-secretase complex, which converts the β-C-terminal fragment (βCTF) to Aβ. Although PS1 plays a central role in directing AD pathogenesis, the mechanisms that regulate PS1 function remain poorly understood.

Researchers explored the regulation of Aβ by PS1. Using in silico analysis, the authors identified a PS1 phosphorylation site, the Ser367 residue, as well as the enzyme responsible for the phosphorylation. In cultured cells, inhibition of the phosphorylating enzyme resulted in a reduction of PS1-Ser367 phosphorylation and an increase in Aβ levels.

Subsequent analysis in transgenic mice in which the Ser residue was mutated to an Ala residue revealed that the mice exhibited significant increases in βCTF and Aβ levels. Further, the mutation was linked to impaired autophagic degradation of βCTF, resulting in the fragment’s accumulation and increased Aβ peptide and plaque levels, suggesting that phosphorylation of PS1 on Ser367 might contribute to autophagic degradation of βCTF and associated reduction in Aβ levels.

 According to the authors, PS1 might play a multifunctional role in modulating Aβ levels.

In a related article , the authors report the molecular mechanism by which PS1 influences βCTF degradation. The authors used transmission EM to examine neurons in PS1-S367A mutant mice to uncover how PS1 phosphorylation regulates autophagy of βCTF.

The analysis revealed that PS1 phosphorylated at Ser367 bound the protein Annexin A2, whereas nonphosphorylated PS1 did not bind the protein. In turn, Annexin A2 facilitated the binding of two SNARE proteins that modulate autophagosome–lysosome fusion.

According to the authors, PS1 phosphorylation at Ser367 promotes βCTF degradation by stimulating such fusion. Taken together, the findings suggest that PS1 phosphorylation might provide a potential therapeutic target in AD treatment.

http://www.pnas.org/content/early/2017/05/17/1705235114

http://www.pnas.org/content/early/2017/05/17/1705240114