Brain-derived tau oligomer polymorphs: distinct aggregations, stability profiles, and biological activities

Filippa Lo Cascio; Suhyeorn Park; Urmi Sengupta; Nicha Puangmalai; Nemil Bhatt; Nikita Shchankin; Cynthia Jerez; Naomi Moreno; Alice Bittar; Rhea Xavier; Yingxin Zhao; Cankun Wang; Hongjun Fu; Qin Ma; Mauro Montalbano; Rakez Kayed

doi:10.1038/s42003-025-07499-w

Brain-derived tau oligomer polymorphs: distinct aggregations, stability profiles, and biological activities

Commun Biol. 2025 Jan 15;8(1):53. doi: 10.1038/s42003-025-07499-w.

Authors

Filippa Lo Cascio^{1

2}, Suhyeorn Park^{1

2}, Urmi Sengupta^{1

2}, Nicha Puangmalai^{1

2}, Nemil Bhatt^{1

2}, Nikita Shchankin^{1

2}, Cynthia Jerez^{1

2}, Naomi Moreno^{1

2}, Alice Bittar^{1

2}, Rhea Xavier^{1

2}, Yingxin Zhao³, Cankun Wang^{4

5}, Hongjun Fu^{6

7}, Qin Ma^{4

5}, Mauro Montalbano^{8

9}, Rakez Kayed^{10

11}

Affiliations

¹ Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.
² Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
³ Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX, USA.
⁴ Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
⁵ Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁶ Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
⁷ Chronic Brain Injury Program, The Ohio State University, Columbus, OH, USA.
⁸ Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA. [email protected].
⁹ Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA. [email protected].
¹⁰ Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA. [email protected].
¹¹ Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA. [email protected].

PMID: 39809992
DOI: 10.1038/s42003-025-07499-w

Abstract

Aggregation of microtubule-associated tau protein is a distinct hallmark of several neurodegenerative disorders such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). Tau oligomers are suggested to be the primary neurotoxic species that initiate aggregation and propagate prion-like structures. Furthermore, different diseases are shown to have distinct structural characteristics of aggregated tau, denoted as polymorphs. Here, we investigate the structural and functional differences of amplified brain-derived tau oligomers (aBDTOs) from AD, DLB, and PSP. Our results indicate that the aBDTOs possess different structural and morphological features that impact neuronal function, gene regulation, and ultimately disease progression. The distinct tau oligomeric polymorphs may thus contribute to the development of clinical phenotypes and shape the progression of diseases. Our results can provide insight into developing personalized therapy to target a specific neurotoxic tau polymorph.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / metabolism
Brain* / metabolism
Female
Humans
Lewy Body Disease / metabolism
Lewy Body Disease / pathology
Male
Protein Aggregation, Pathological / metabolism
Protein Stability
Supranuclear Palsy, Progressive / metabolism
tau Proteins* / chemistry
tau Proteins* / metabolism

Substances

tau Proteins
MAPT protein, human

Abstract

MeSH terms

Substances

Grants and funding