Alzheimer’s disease (AD) is on a rapid rise in the aged population with typical hallmarks of extracellular Aβ deposits and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau proteins. Positron emission tomography imaging and screening for Aβ peptides and hyperphosphorylated tau in the cerebrospinal fluid are currently considered the ‘gold standard’ to confirm AD. However, the current diagnostic modalities have great limitations as these are highly expensive, difficult to apply in health system set up and often lack reproducibility. Immune/inflammatory responses play a key role in maintaining brain homeostasis, however, disturbances associated with inflammatory responses confirm the role of mediators of inflammatory/immune response in neurodegeneration. The major aim of this study was to investigate abnormalities associated with the immune responses in AD patients and in a mouse model of AD (APP/PS1) and to establish a molecular “fingerprint” specific for early detection of AD. Initially, using next generation sequencing, we investigated the B-cell receptors (BCR) in APP/PS1 and compared with wild type littermates. We observed a higher mutation rate associated with the APP/PS1BCR repertoire. In addition, physicochemical analysis showed that the APP/PS1 BCR repertoire displayed higher instability indices of the clones, suggesting a defect in the immune responses against antigens. Of importance, most of the somatic hypermutation homed to CDR1, CDR2 as well as FR2 and FR3Finally, our mass spectrometry analysis indicated that most of the identified proteins were associated with the immune system and were significantly down regulated. Taken together, these results confirm a generalized faulty immune system in AD and more specifically, highlight a defective isotype switch and affinity maturation responsible for the molecular immunological diversity. Our novel findings and strategies will help us pave the way to better understand the crucial role of Immune system in AD and develop a robust early diagnostic test for AD.
What will audience learn from your presentation?
- Our current study is focused on developing a diagnostic test for AD that has been long awaited.
- Our current study helps provide insights into somatic hypermutation and isotype switch associated with AD,
- Such a study has never been published till date and opens new horizons in the diagnosis of AD