Aged Alzheimer’s disease brains exhibit numerous Aβ but only few tau prions

Identification: Condello, Carlo


Aged Alzheimer's disease brains exhibit numerous Aβ but only few tau prions
Carlo Condello1,2,†, Atsushi Aoyagi1,3,†, Jan Stöhr1,2, Glenda Halliday4, Sjoerd van Duinen5, Martin Ingelsson6, Lars Lannfelt6, Caroline Graff7, Thomas D. Bird8, C. Dirk Keene9, William W. Seeley2,10, William F. DeGrado11, and Stanley B. Prusiner1,2 
1Institute for Neurodegenerative Diseases, University of California, San Francisco, CA; 2Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA; 3Daiichi Sankyo Co., Ltd., Tokyo, Japan;  4School of Medical Science, University of New South Wales, Sydney, Australia;  5Leiden University Medical Center, Leiden, The Netherlands; 6Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden; 7Department of Neurobiology, Karolinska Institute, Huddinge, Sweden; 8Department of Neurology, University of Washington, Seattle, WA; 9Department of Neuropathology, University of Washington School of Medicine, Seattle, WA; 10Department of Pathology, University of California, San Francisco, CA; 11Department of Pharmaceutical Chemistry, University of California, San Francisco, CA
A.A. and C.C. contributed equally
Aβ and tau aggregation contribute to pathogenesis of Alzheimer's disease (AD).  However, it is unclear whether Aβ plays only an early role, or whether ongoing engagement of infective Aβ prions continues with disease progression. Also, distinguishing between inert amyloids versus active spreading prions is difficult. Thus, we devised a cellular bioassay, enabling a parallel comparison of tau and Aβ prion levels in post mortem human samples. All individuals had significant Aβ prion levels at death; interestingly the longest-lived individuals showed a slight reduction in post mortem Aβ prion levels. Tau prion levels showed a greater decrease with life span, and half of the >80 year-old patients had very low tau prion levels despite significant neurofibrillary tau deposits. This trend was observed over a wide range of etiological forms of AD. Thus, familial and sporadic AD can now be seen as a continuous spectrum, with the defining feature being the presence of active tau and Aβ prions. Furthermore, APOE ε4 alleles known to predispose towards AD appeared to increase tau but not Aβ prions in the elderly. These data illustrate the interplay between prion strain aggressiveness and host factors in defining longevity, and identify the prion form as a target for therapeutics.


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