In a recent study, a team of researchers has discovered that a naturally occurring protein called Lipocalin-type prostaglandin D synthase (L-PGDS) prevents, and can destroy, the protein aggregates associated with Alzheimer’s disease.
Surprisingly common and with critical functions
L-PGDS is a common protein, second only to albumin, in the human brain. It provides several critical functions, including regulation of processes and protection against further damage from ischemic strokes. It has been shown to be a molecular chaperone, preventing amyloid beta from forming the deadly aggregates associated with Alzheimer’s, and, perhaps most importantly, it has been shown to destroy aggregates that already exist. Not surprisingly, people who suffer from Alzheimer’s disease lack adequate amounts of this critical protein.
This function of keeping proteins from forming amyloid aggregates preserves proteostasis, and its loss is one of the primary hallmarks of aging. While Alzheimer’s is far from the only disease related to a loss of proteostasis, it is one of the most well-known and the most tragic, and the researchers point out that, if a cure is not found, it will affect more than 13.8 million people in the United States by the year 2050.
Misfolding of Amyloid ß (Aß) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) protein to act as a disaggregase on the pre-formed fibrils of Aß(1–40), abbreviated as Aß40, and Aß(25–35) peptides, in addition to inhibiting the aggregation of Aß monomers. Furthermore, our proteomics results indicate that L-PGDS can facilitate extraction of several other proteins from the insoluble aggregates extracted from the brain of an Alzheimer’s disease patient. In this study, we have established the mode of binding of L-PGDS with monomeric and fibrillar Aß using Nuclear Magnetic Resonance (NMR) Spectroscopy, Small Angle X-ray Scattering (SAXS), and Transmission Electron Microscopy (TEM). Our results confirm a direct interaction between L-PGDS and monomeric Aß40 and Aß(25–35), thereby inhibiting their spontaneous aggregation. The monomeric unstructured Aß40 binds to L-PGDS via its C-terminus, while the N-terminus remains free which is observed as a new domain in the L-PGDS-Aß40 complex model.
This study provides a new angle of Alzheimer’s research, suggesting that a common protein is responsible for its prevention and that inadequate levels of this protein contribute to Alzheimer’s.
However, of course, the effects of L-PDGS have only been tested in vitro; L-PDGS upregulation has not been tested in mice, let alone people. More research will need to be done to determine whether or not it is feasible to develop L-PDGS upregulation as a therapy for preventing or treating this deadly neurodegenerative disease.