NEW PUBLICATION

Happy to share our latest publication in collaboration with Dr. Lucia Chávez- Gutiérrez in eLife.

A new hypothesis of the role of amyloid beta peptide in Alzheimer's disease is formulated.

p75CTF accumulation would be a product of γ-secretase inhibition by Aβ-peptide.

The amyloid hypothesis of Alzheimer's disease is the oldest and the widest accepted, but also the most disputed, of all the molecular causes of the AD. In this hypothesis the accumulation of the so called amyloid peptide, a pro-aggregation peptide fragment produced by the cleavage of the APP protein by the γ-secretase complex, will form extracellular protein aggregates, called amyloid, that would disrupt the normal functions of the neurons in the CNS causing presenil neurodegeneration and ultimately Alzheimer's disease. Although the participation of the APP and the γ-secretase complex in the AD is unquestionable, based on genetic evidencies showing that only Familiar AD is caused by mutations on APP, PSEN1 and PSEN2 (being PSEN the catalytic components of the γ-secretase complex), the molecular mechanism by which amyloid peptide is causing so much harm has not been solved clearly. Here we provide a new mechanism based on the enzymatic activity of the γ-secretase complex. The laboratory of Dr. Chavez-Gutierrez described that Aβ peptide, when in high concentrations, inhibitis the activity of the γ-secretase in vitro and in vivo. Interestingly only the human Aβ-142 is able to do such inhibition, and not shorter Aβ peptides, like Aβ17-35 or the murine Aβ1-42. The consequences of such inhibition is the accumulation of C-terminal fragments of γ-secretase substrates, not only the APP-CTF itself but also others like cadherin, or p75-CTF. Here is where our collaboration materializes showing that Aβ induces the accumulation of p75CTF not only in PC12 cells but also in primary culture of basal forebrain cholinergic neurons, leading to cell death in the absence of TrkA activation.

Taking into account that the neurodegeneration of the cholinergic system precedes AD pathology and p75 is highly expressed during all the life in the BFCNs, this paper confirmed p75 as good target in the treatment of AD.

Publication:

Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.

Zoltowska KM, Das U, Lismont S, Enzlein T, Maesako M, Houser MCQ, Franco ML, Özcan B, Gomes Moreira D, Karachentsev D, Becker A, Hopf C, Vilar M, Berezovska O, Mobley W, Chávez-Gutiérrez L.

eLife. 2024 Jul 19;12:RP90690. doi: 10.7554/eLife.90690.PMID: 39027984