Age‐related resident memory CD8 T cells link amyloid to NFTs and neurodegeneration in mice and are modulated in AD and MCI blood: Development of new models and analysis methods/neuroinflammation. (7th December 2020)

• Record Type: Journal Article
• Authors: Wheeler, Christopher J.; Panwar, Akanksha; Rentsendorj, Altan; Cordner, Ryan; Yeager, Nicole; Jin, Lee‐Way; Koronyo, Yosef; Koronyo‐Hamaoui, Maya; Black, Keith L.; Van Dam, Debby; De Deyn, Peter Paul; Yamamoto, Vicky; Trujillo, Kristina
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.040612
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: While autosomal dominant mutations that promote amyloid deposition guarantee rare genetically‐determined Alzheimer's disease (AD), discrete factors promoting more prominent sporadic AD have not been identified. Evidence from mice, and more recently from a patient resistant to autosomal dominant AD, suggests that an age‐sensitive factor missing from mice links amyloid deposition to NFTs and neurodegeneration in AD, and is critical for AD development. We previously engineered mice that possess human‐like predominance of an age‐related resident memory CD8 T cell population ( hi TRM mice), and exhibit antigen‐specific CD8 T cell accumulation in brain, as well as sporadic amyloid deposition linked to NFT‐like structures and neurodegeneration. Method: We used CD8 T cell antigen specificity within the hi TRM model to generate pHLA reagents that identify analogous antigen‐specific memory CD8 T cells in humans, and used them to quantify their levels in blood and/or brain of HLA‐A2+, normal aging, MCI with or without AD biomarkers (AD‐associated and non‐associated MCI, respectively), and confirmed late‐onset AD cohorts. Cognitive performance was also assessed using the MoCA test in sub‐cohorts of MCI patients. Result: We show that antigen‐specific hi TRM analogues were increased in perivascular and cortical regions of human AD relative to normal aging brain (13 vs. 3%; P < 0.01), but decreased in blood of AD‐associated MCI and late‐onset AD patients (1.3 and 0.7%, respectively; 3.4% in normal controls; P < 0.00009), and correlated with cognitive impairment in MCI (r = 0.828; P < 0.005). Receiver operating characteristic (ROC) analysis of levels of these analogues in blood revealed area under the curve (AOC) of 0.715, 0.803, and 0.862 for non‐associated, AD‐associated, and AD, respectively. Conclusion: Our results identify antigen‐specific memory CD8 T cells, a factor critically linking amyloidopathy to NFTs and which dominantly promote the development of AD‐like neurodegeneration in mice, as unique blood‐based biomarkers that accurately track the AD continuum in patients. As such, these cells may play a similar role in AD pathoetiology in mice and sporadic human AD. These cells thus represent novel biometric and therapeutic candidates for sporadic AD.