A pair of new studies have found that Alzheimer''s disease is linked to the production of short to long amyloid peptides in their brain.
The A peptides that infamously aggregate in the brains of Alzheimers suffer are derived from the -secretase cleavage of the amyloid precursor protein. While many mutations in the catalytic subunits of the enzyme, the age at which they begin to take their toll varies dramatically from one mutation to the next. Two recent studies examined what impact mutations on the whole repertoire of A peptides churned out by the secretase.
- Two studies related the full repertoire of A peptides to age at onset of AD.
- Earlier AAO was tied to low A37/A42, or A (37+38+40)/(42+43).
- These ratios tracked more closely with AAO than did A42/40.
One study, led by Dennis Selkoe of the Brigham and Women''s Hospital in Boston, found that lower ratios of A37 to A42 correlated with an earlier age at the start of the disease, along with increased A (37+38)/(42+43) ratio compared to AAO in people with chronic Alzheimer''s.
In either study, the A42/40 ratio did not always follow AAO. Overall, findings suggest that A peptide ratios that reflect the hobbling of-secretase processivity might serve as more sensitive biomarkers for disease onset and severity.
These findings demonstrate the fundamental significance of a comprehensive review of A peptide profiles in deciphering AD pathogenesis, according to Chavez-Gutierrez.
The substratethe C99 fragment of APPvia two consecutive cleavage events: endoprotease cleavage produces the long, membrane-anchored peptides A48 or A49, off which -cleavage then slices three to four amino acids at a time until the remaining peptide is removed from the plasma membrane. In this manner, two product lines of A peptides are identified: A 4946434037 and A 48454239, 38 or 37.
The fact that PSEN1 has advanced its processive capabilities, thus leading to a similar overproduction of the longer, aggregation-prone peptides A42 and A43 at the expense of the shorter ones, according to scientists (Szaruga et al., 2017). Most research in the field have focused on A42, but have yet to conclude that the A42/40 ratio reflects disease severity.
Might determining the whole A peptide repertoire as described in the Selkoes group? The first author Lei Liu and his colleagues used immunoassays to measure all six A peptides produced by cells expressing different PSEN1 mutations. In a matter of words, they found that the A37/42 ratio correlated more strongly and consistently with the AAO associated with each of more than 100 PSEN1 mutations.
In sporadic AD, this ratio of short-to-long peptides proved useful. A37/42 compared individuals with a low or high A burden in both brain tissue and CSF, while separating individuals who were cognitively normal from those who had been impaired.
In a Chavez-Gutierrezs study, first authors Dieter Petit and colleagues measured the number of A peptides released by cells expressing any of the 25 different familial AD mutations in PSEN1. Using an unbiased statistical analysis, they found that the A (37+38+40)/(42+43) ratio correlated with the AAO associated with each mutation.
The analysis found that when the scientists used this ratio to estimate the AAO of PSEN1 mutations whose pathogenicity was unknown, such as those identified in one person with AD, the estimated AAO fell within six years of the reported AAO for most mutations. Nevertheless, other genetic influences, such as the ApoE genotype, might also be to blame.
According to Rebecca Gabriele, Selina Wray, and Charlie Arber of University College London, the study highlights the importance that diverse A species play in AD pathology. Moreover, AAO is strongly linked to a longer, more aggregation-prone A species, suggesting that shifting A profiles to shorter and less amyloidogenic peptides might be a viable therapeutic approach.
The shorter A species are getting a second wind (Jan 2022 news;Feb 2022 news); however, some pharma firms are believed to have ended their efforts to develop such compounds.Jessica Shugart
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