Corpora amylacea negatively correlate with hippocampal tau pathology in Alzheimer's disease

Julian D Dallmeier; Ryan Gober; Regina T Vontell; Ayled Barreda; Daniel A Dorfsman; David A Davis; Xiaoyan Sun; Daniel Brzostowicki; Illiana Bennett; Susanna P Garamszegi; Connor M Wander; Todd Cohen; William K Scott

doi:10.3389/fnins.2024.1286924

Corpora amylacea negatively correlate with hippocampal tau pathology in Alzheimer's disease

Front Neurosci. 2024 Feb 29:18:1286924. doi: 10.3389/fnins.2024.1286924. eCollection 2024.

Authors

Julian D Dallmeier¹, Ryan Gober¹, Regina T Vontell^{1

2}, Ayled Barreda¹, Daniel A Dorfsman³, David A Davis^{1

2}, Xiaoyan Sun^{1

2}, Daniel Brzostowicki¹, Illiana Bennett¹, Susanna P Garamszegi¹, Connor M Wander⁴, Todd Cohen⁴, William K Scott^{1

3}

Affiliations

¹ Brain Endowment Bank, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States.
² Department of Neurology, Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, United States.
³ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States.
⁴ Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Abstract

Introduction: Severity and distribution of aggregated tau and neurofibrillary tangles (NFT) are strongly correlated with the clinical presentation of Alzheimer's disease (AD). Clearance of aggregated tau could decrease the rate of NFT formation and delay AD onset. Recent studies implicate corpora amylacea (CA) as a regulator of onset or accumulation of tau pathology. Normally, CA clear brain waste products by amassing cellular debris, which are then extruded into the cerebrospinal fluid to be phagocytosed. The proper functioning of CA may slow progression of AD-associated NFT pathology, and this relationship may be influenced by amount and distribution of phospho-tau (pTau) produced, age, sex, and genetic risk.

Objective: The goal of this study was to determine if CA size and number are associated with hippocampal location and local pTau severity while accounting for variations in age, sex, and genetic risk.

Methods: Postmortem brain hippocampal tissue sections from 40 AD and 38 unaffected donors were immunohistochemically stained with AT8 (pTau) and counter stained with periodic acid Schiff (PAS). Stained sections of the CA1 and CA3 regions of the hippocampus were analyzed. The percent area occupied (%AO) of CA, pTau, and NFT was calculated. Pairwise comparisons and regression modeling were used to analyze the influence of age, pTau %AO, and genetic risk on %AO by CA in each region, separately in donors with AD and unaffected donors.

Results: CA %AO was significantly higher in the CA3 region compared to CA1 in both groups. A significant negative correlation of CA %AO with both pTau %AO and neurofibrillary tangle %AO in the CA3 region of AD brain donors was found. Regression analysis in the CA3 region revealed a significant negative association between CA with both pTau and age.

Conclusion: We found an increase of CA in the CA3 region, compared to CA1 region, in AD and unaffected donors. This may suggest that the CA3 region is a hub for waste removal. Additionally, the negative correlation between %AO by CA and NFT in the CA3 region of the hippocampus in donors with AD suggests CA could play a role in AD pathologic progression by influencing tau clearance.

Keywords: APOE; Alzheimer’s disease; brain; corpora amylacea; neurofibrillary tangles; neuropathology; wasteosomes.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was generously supported by the National Institute of Health (NIH) through an F31 Individual Training Grant awarded (1F31AG077721-01A1) to JD. We extend our appreciation to the NIH for their commitment to advancing Alzheimer’s Disease research.