PHF-tau propagation in the presence of Amyloid ß pathology
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1
UNI (ULB Neuroscience Institute), Faculty of medicine, Université Libre de Bruxelles, Belgium
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2
AP-HP, Hôpital de la Pitié-Salpêtrière, France
Alzheimer’s disease (AD) is the most common form of dementia characterised by a progressive cognitive decline. Pathologically, it is characterized by two hallmarks: amyloid plaques mostly consisting of β-amyloid peptide (Aβ) derived from the successive cleavage of the amyloid precursor protein (APP), and neurofibrillary tangles (NFTs) [6]. NFTs are formed by the aggregation of paired helical filaments (PHF), composed of abnormally phosphorylated and aggregated microtubules associated tau proteins [3]. NFTs correlate strongly with the cognitive decline and can also be found in a group of neurodegenerative diseases called tauopathies [4]. The importance of tau in mediating the toxicity of Aβ peptides has been demonstrated in tau knock-out neurons being resistant to Aβ-associated toxicity [11]. Deletion of murine tau expression rescues excitotoxicity in transgenic APP mice [8,12]. We have previously reported that tau deletion reduced Aβ load [9] in 5xFAD mice overexpressing human APP (K670N/M671L, I716V, and V717I) and PS1 (M146L and L286V) [10]. In contrary, crossing 5xFAD with Tg30 overexpressing human double mutant tau exacerbated tau pathology [7]. Nevertheless it remains elusive how tau pathology propagation is associated with amyloid pathology. In this study, we hypothesized that there may be an association between pathological tau seeding and Aβ.
We have previously shown that stereotaxic injection of PHF obtained from AD brain induced Argyrophilic grains composed of hyperphosphorylated murine tau in wild-type (WT) mouse brains [2]. In this study, we conducted stereotaxic injection of human PHF into the brains of WT and 5xFAD mice. Stereotaxic injection of PHF induced aggregation of endogenous murine tau into gallyas-positive grains in the cortex and corpus callosum of both WT and 5xFAD mice. This Argyrophilic grain pathology seems to be more important in 5xFAD compared to WT mice as the grains could be detected not only in the ipsilateral hemisphere (left) but also in the contralateral hemisphere (right) in 5xFAD mouse brains. These grains were never present when injected with human control material obtained from non-demented individuals.
Finally, we carefully analysed the association of amyloid and tau pathologies in human post-mortem AD brains by CLARITY [1,5] and we found that mature focal amyloid plaques contained more tau-positive dystrophic neurites than diffuse plaques. Taken together, this study shed lights on the acceleration of tau pathology propagation by amyloid pathology.
Summary
Alzheimer's disease causes progressive memory loss and behavioral changes, and it even causes many difficulties in daily tasks. It is characterised by the appearance of two abnormal lesions called amyloid plaques and tangles, responsible for the loss of neurons 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 tangle formation in animal models.
Résumé en Français
La maladie d’Alzheimer est caractérisée par le développement de deux lésions cérébrales responsables de la mort des cellules nerveuses: les « plaques amyloïdes», composées d’une molécule appelée amyloïde-beta, et les « dégénérescences neurofibrillaires », composées d’agrégats d’une protéine appelée tau. Afin de comprendre si ces deux lésions interagissent lors de leur développement, nous avons injecté des protéines tau dans des souris développant ou non des plaques amyloïdes. Ces souris ont développé des agrégats de protéine tau, indiquant que les protéines tau anormales ont des capacités de propagation dans le cerveau dans la maladie d’Alzheimer.
Samenvatting in het Nederlands:
De ziekte van Alzheimer wordt gekenmerkt door twee hersenletsels die verantwoordelijk zijn voor het afsterven van hersencellen: de “amyloïde neerslag” bestaande uit een molecule amyloïde-beta genoemd en de “neurofibrillaire degeneratie” bestaande uit aggregaten van een tau genoemde proteïne. Om te begrijpen of deze beide letsels interageren tijdens hun ontwikkeling hebben we tau proteïnes geïnjecteerd bij muizen die al dan niet een amyloïde neerslag ontwikkelden. Deze muizen maakten tau proteïne aggregaten aan, wat aantoont dat abnormale tau proteïnes zich in de hersenen kunnen propageren bij de ziekte van Alzheimer.
References
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2 Audouard E, Houben S, Masaracchia C et al. (2016) High molecular weight PHF from Alzheimer brain induce seeding of wild-type mouse tau into an argyrophilic 4R tau pathology in vivo. Am J Pathol In press
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9 Leroy K, Ando K, Laporte V et al. (2012) Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice. Am J Pathol 181: 1928-1940
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12 Roberson ED, Scearce-Levie K, Palop JJ et al. (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 316: 750-754
Keywords:
Alzheimer’s disease,
PHF-tau,
Stereotaxic injection,
5xFAD,
tau spreading,
CLARITY
Conference:
6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.
Presentation Type:
Poster Presentation
Topic:
Brain and brain diseases: between heredity and environment
Citation:
Vergara
C,
Houben
S,
Vanden Dries
V,
Yilmaz
Z,
Suain
V,
De Decker
R,
Duyckaerts
C,
Boom
A,
Leroy
K,
Ando
K and
Brion
J
(2016). PHF-tau propagation in the presence of Amyloid ß pathology.
Conference Abstract:
6th Belgian Brain Congress.
doi: 10.3389/conf.fnagi.2016.03.00021
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Received:
29 Jun 2016;
Published Online:
01 Jul 2016.
*
Correspondence:
MD, PhD. Jean-Pierre Brion, UNI (ULB Neuroscience Institute), Faculty of medicine, Université Libre de Bruxelles, Brussels, Belgium, jpbrion@ulb.ac.be