New Peptide Ratio Might Give Clues to Alzheimer's Onset

A pair of new studies has identified that the onset of Alzheimer's disease is linked to the ratio of short to long amyloid peptides produced in their brain. 

The Aβ peptides that infamously aggregate in the brains of people with Alzheimer’s disease are products of γ-secretase cleavage of the amyloid precursor protein. Many mutations in the catalytic subunits of the enzyme, as well as its substrate, can cause familial AD, yet the age at which they begin to take their toll varies strikingly from one mutation to the next. Two recent studies assessed what impact mutations have on the full repertoire of Aβ peptides churned out by the secretase. Both found, essentially, that a person's ratio of short to long peptides had a lot to do with when their symptoms started.

One, published March 12 in Alzheimer’s and Dementia and led by Dennis Selkoe of Brigham and Women’s Hospital in Boston, reported that lower ratios of Aβ37 to Aβ42 correlated with earlier age at onset (AAO) in people with familial AD, and also with greater Aβ burden and more cognitive impairment in people with sporadic disease. The Aβ37/42 ratio outperformed the Aβ42/40 ratio, which has become a staple biomarker for AD and has entered clinical practice. The other study was led by Lucia Chávez-Gutiérrez at KU Leuven in Belgium and published April 1 in Molecular Psychiatry. It found that ratios of short to long peptides, particularly the Aβ (37+38+40)/(42+43) ratio, best correlated with AAO in people carrying known ADAD mutations, and even predicted AAO in variants with unclear pathogenicity.

Notably, the Aβ42/40 ratio did not consistently track with AAO in either study. Overall, the findings suggest that Aβ peptide ratios that reflect the hobbling of γ-secretase processivity could serve as more sensitive biomarkers for disease onset and severity.

“Taken together, these studies support the critical importance of comprehensive evaluation of Aβ peptide profiles in deciphering AD pathogenesis,” noted Chávez-Gutiérrez.

Gamma-secretase handles its substrate—the C99 fragment of APP—via two consecutive cleavage events: ε endoprotease cleavage produces the long, membrane-anchored peptides Aβ48 or Aβ49, off which γ-cleavage then slices three to four amino acids at a time until the remaining peptide is released from the plasma membrane. In this manner, two product lines of Aβ peptides are released: Aβ 49→46→43→40→37 and Aβ 48→45→42→39, 38 or 37.

Familial AD mutations in PSEN1 destabilize the γ-secretase complex, hobbling its processive function, and leading to relative overproduction of the longer, aggregation-prone peptides Aβ42 and Aβ43 at the expense of the shorter peptides (Szaruga et al., 2017). Most studies in the field have focused on Aβ42, yet have come to different conclusions about how the Aβ42/40 ratio reflects disease severity.

Might accounting for the full Aβ peptide repertoire be more useful? In Selkoe’s group, first author Lei Liu and colleagues used immunoassays they had developed to measure all six Aβ peptides produced by cells expressing different PSEN1 variants. In a nutshell, they found that, compared to Aβ42/40, the Aβ37/42 ratio correlated more robustly and consistently with the AAO associated with each of more than 100 PSEN1 mutations.

This ratio of short-to-long peptides also proved informative in sporadic AD. In either brain tissue or in CSF, Aβ37/42 distinguished between people with low and high Aβ burden, and also separated people who were cognitively normal from those who had been impaired.

In Chávez-Gutiérrez’s study, first author Dieter Petit and colleagues measured the spectrum of Aβ peptides released by cells expressing any of 25 different familial AD mutations in PSEN1. Using an unbiased statistical approach, they found that the Aβ (37+38+40)/(42+43) ratio correlated with the AAO associated with each mutation.

When the scientists used this ratio to estimate the AAO of PSEN1 mutations whose pathogenicity was unclear, such as those identified in only one person with AD, the estimated AAO fell within six years of the reported AAO for most mutations. In some exceptions where the estimate was further off the mark, other genetic influences, such as ApoE genotype, could account for the discrepancy. The findings suggest not only that changes in the Aβ (37+38+40)/(42+43) ratio—i.e., γ-secretase processive activity—track closely with AAO, but also that additional genetic and/or environmental factors tweak this relationship.

“Overall, the study further confirms the crucial role diverse Aβ species play in AD pathology, and that Aβ profiles of several Aβ species (not only Aβ40 and Aβ42) best predict AAO,” wrote Rebecca Gabriele, Selina Wray, and Charlie Arber of University College London in a joint comment to Alzforum. “Moreover, AAO is strongly linked to longer, more aggregation-prone Aβ species, suggesting that shifting Aβ profiles toward shorter and less amyloidogenic peptides could be a valid therapeutic approach.”

More generally, the shorter Aβ species are getting a second wind (Jan 2022 news; Feb 2022 news). One γ-secretase modulator is poised to enter clinical trials (Rynearson et al., 2021); alas, most pharma companies are believed to have ended their efforts to develop such compounds.—Jessica Shugart

References: