Unique Pathology in the Locus Coeruleus of Individuals with Down Syndrome

Article type: Research Article

Authors: Saternos, Hannah^a | Hamlett, Eric D.^b | Guzman, Samuel^c | Head, Elizabeth^d | Granholm, Ann-Charlotte^a | Ledreux, Aurélie^{a; *}

Affiliations: [a] Department of Neurosurgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA | [b] Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA | [c] Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA | [d] Department of Pathology and Laboratory Medicine, University of California at Irvine, Irvine, CA, USA

Correspondence: [*] Correspondence to: Aurélie Ledreux, PhD, University of Colorado Anschutz Medical Campus, Department of Neurosurgery, 12700 E 19th Ave, Aurora, CO 80045, USA. Tel.: +1 303 724 6000; E-mail: Aurelie.Ledreux@cuanschutz.edu.

Abstract: Background:Down syndrome (DS) is one of the most commonly occurring chromosomal conditions. Most individuals with DS develop Alzheimer’s disease (AD) by 50 years of age. Recent evidence suggests that AD pathology in the locus coeruleus (LC) is an early event in sporadic AD. It is likely that the widespread axonal network of LC neurons contributes to the spread of tau pathology in the AD brain, although this has not been investigated in DS-AD. Objective:The main purpose of this study was to profile AD pathology and neuroinflammation in the LC, comparing AD and DS-AD in postmortem human tissues. Methods:We utilized immunofluorescence and semi-quantitative analyses of pTau (4 different forms), amyloid-β (Aβ), glial, and neuronal markers in the LC across 36 cases (control, DS-AD, and AD) to compare the different pathological profiles. Results:Oligomeric tau was highly elevated in DS-AD cases compared to LOAD or EOAD cases. The distribution of staining for pT231 was elevated in DS-AD and EOAD compared to the LOAD group. The DS-AD group exhibited increased Aβ immunostaining compared to AD cases. The number of tau-bearing neurons was also significantly different between the EOAD and DS-AD cases compared to the LOAD cases. Conclusions:While inflammation, pTau, and Aβ are all involved in AD pathology, their contribution to disease progression may differ depending on the diagnosis. Our results suggest that DS-AD and EOAD may be more similar in pathology than LOAD. Our study highlights unique avenues to further our understanding of the mechanisms governing AD neuropathology.

Keywords: Alzheimer’s disease, amyloid-beta, astrocyte, Down syndrome, locus coeruleus, microglia, tau

DOI: 10.3233/JAD-240043

Journal: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 541-561, 2024