Amyloid pathology enhances seeding and propagation of fibrillar endogenous non-mutant tau in vivo
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1
Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute (UNI), Belgium
The topographical development of tau pathology in Alzheimer’s Disease (AD) progresses by following neuroanatomically connected areas, suggesting that spreading of tau pathology occurs by transmission of abnormal tau between synaptically connected cells. Both, neuropathological analysis in AD and experimental evidence in transgenic models overexpressing FTDP-17 mutant tau, suggest that amyloid pathology can accelerate the development of tau pathology, yet the involved mechanisms are not understood. To investigate a potential role of Aß pathology in accelerating the spreading of tau pathology independently of the overexpression of a FTDP-17 mutant tau, we compared development of tau pathology after stereotaxic injection in the somatosensory cortex of short-length native human PHF. We used four mouse lines, namely non-transgenic wild-type, APP/PS1 overexpressing human mutant APP and PS1, APP knock-out mice and tau knock-out mice. Gallyas and phosphotau positive grain-like tau inclusions developed in wild-type, APP/PS1 and APP knock-out mice but not in tau knock-out mice. Ultrastructural analysis demonstrated that these tau grains were intracellular and were made of 20 nm straight filaments. These tau grains seeded by human PHF-tau were composed only of endogenous murine tau. Ipsilateral anteroposterior and contralateral spreading of these tau grains in the cortex was more important in APP/PS1 than in wild-type mice. Importantly, the formation of enlarged, tau positive, plaque-associated dystrophic neurites was observed in APP/PS1 mice injected with human PHF but never in non-injected APP/PS1 mice. These data demonstrate in vivo that the presence of Aß pathology enhances experimentally induced tau seeding of endogenous, wild-type tau expressed at physiological level, and demonstrate the fibrillar nature of heterotopically seeded endogenous tau. These observations strongly support the hypothesis that a cross-talk between Aß and tau can enhance the development of tau pathology in AD through increased tau spreading.
Summary:
Alzheimer's disease is the main cause of dementia, causing progressive memory decline and behavioral changes affecting daily tasks. It is characterised by the appearance of two abnormal lesions called amyloid plaques and tangles, responsible for the neuronal loss during the disease. Amyloid plaques are composed of a small protein called amyloid-beta, and tangles are formed by the aggregation of another protein called tau. Here we study how amyloid-beta affects the aggregation of tau to form tangles in genetically modified animal models.
Keywords:
Alzheimer's disease,
tau seeding,
PHF,
Aβ,
Prion-like tau propagation
Conference:
Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018.
Presentation Type:
e-posters
Topic:
NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE
Citation:
Vergara
C,
Houben
S,
Suain
V,
Yilmaz
Z,
De Decker
R,
Mansour
S,
Boom
A,
Leroy
K,
Ando
K and
Brion
J
(2019). Amyloid pathology enhances seeding and propagation of fibrillar endogenous non-mutant tau in vivo.
Front. Neurosci.
Conference Abstract:
Belgian Brain Congress 2018 — Belgian Brain Council.
doi: 10.3389/conf.fnins.2018.95.00042
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Received:
14 Aug 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
PhD. Cristina Vergara, Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute (UNI), Brussels, Brussels, Belgium, Cristina.Vergara.Panos@ulb.ac.be
Prof. Jean-Pierre Brion, Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute (UNI), Brussels, Brussels, Belgium, jpbrion@ulb.ac.be