▎ WuXi AppTec content team editor
In the field of Alzheimer's disease research, the amyloid cascade hypothesis is one of the most popular hypotheses. According to this theory, β amyloid (Aβ) fragments are too much or not cleared in time, resulting in soluble Aβ oligomers and insoluble amyloid deposits in the brain, forming amyloid plaques.
Most of the Aβs that accumulate in the brains of Alzheimer's disease patients are long fragments with relatively large numbers of amino acids, that is, Aβ42 and Aβ40. Therefore, the detection of the ratio of Aβ42/Aβ40 in plasma or cerebrospinal fluid has become a biomarker into clinical practice.
Image credit: 123RF
However, a new study recently published in Alzheimer's and Dementia, a professional journal for Alzheimer's research, found that the ratio of Aβ37 in short segments to Aβ42 in long fragments may be used as a biomarker to better predict Alzheimer's disease compared to the ratio of Aβ42/Aβ40.
In the study, Dr. Lei Liu and colleagues at Brigham and Women's Hospital at Harvard University found that the lower Aβ37/Aβ42 ratio in cerebrospinal fluid correlated with the earlier age at which familial Alzheimer's disease developed symptoms and the more severe cognitive impairment of sporadic Alzheimer's disease.
In this study, the scientists used the immunoassay they developed to measure all six lengths of Aβ peptides produced by presenilin-1 mutant cells. Aβ peptide fragments are formed by multiple cleavages of amyloid precursors (APP) through γ secretory enzymes. γ secretases cleave three or four amino acids at a time, and when certain mutations occur in the catalytic subunits (e.g., progerin) or substrates of γ secretase complexes, the processing function of the γ-secretase complexes is impaired, resulting in an overproduction of longer, easily aggregated Aβ42 or Aβ43, and relatively few short fragments such as Aβ37.
The researchers found that the ratio of short peptides to long peptides not only distinguishes progerin mutant cells from normal cells, but also in more than 100 mutant cells, the Aβ37/42 ratio can more sensitively detect progerin/γ-secretory enzyme dysfunction compared with Aβ42/40, meaning that the Aβ37/42 ratio can be used to assess the age of onset in familial Alzheimer's.
This ratio of short peptides to long peptides also demonstrates the role of being used to evaluate sporadic Alzheimer's disease. The researchers compared brain tissue and cerebrospinal fluid between alzheimer's patients and cognitively normal subjects and found that the ratio of Aβ37/42 could better distinguish between cognitively normal people and cognitively impaired people than Aβ42/40.
The paper concludes that measuring this new ratio of Aβ37/42, combined with other hallmark pathological features of Alzheimer's disease (such as highly phosphorylated tau protein), is expected to provide a highly differentiated liquid detection biomarker for Alzheimer's disease.
Resources:
[1] Lei Liu et al., (2022) Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. Doi: 10.1002/alz.12646
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