Prodromal neuroinflammatory, cholinergic and metabolite dysfunction detected by PET and MRS in the TgF344-AD transgenic rat model of AD: a collaborative multi-modal study

• Published in: Theranostics 2021-01, Vol.11 (14), p.6644-6667
• Main Authors: Chaney, Aisling M, Lopez-Picon, Francisco R, Serrière, Sophie, Wang, Rui, Bochicchio, Daniela, Webb, Samuel D, Vandesquille, Matthias, Harte, Michael K, Georgiadou, Christina, Lawrence, Catherine, Busson, Julie, Vercouillie, Johnny, Tauber, Clovis, Buron, Frédéric, Routier, Sylvain, Reekie, Tristan, Snellman, Anniina, Kassiou, Michael, Rokka, Johanna, Davies, Karen E, Rinne, Juha O, Salih, Dervis A, Edwards, Frances A, Orton, Llwyd D, Williams, Stephen R, Chalon, Sylvie, Boutin, Hervé
• Format: Article
• Language: English
• Subjects: Age; Alzheimer's disease; Animal cognition; animal models; Chemical Sciences; Experiments; Laboratory animals; Life Sciences; magnetic resonance spectroscopy; Medicinal Chemistry; Mutation; neuroinflammation; Organic chemistry; Pathology; positron emission tomography; Research Paper
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.56059

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing APP and PSEN1 mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease. Methods: TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [18F]DPA-714 (TSPO, neuroinflammation), [18F]Florbetaben (Aβ) and [18F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[18F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aβ, NeuN, NeuroChrom) and Tau (S)-[18F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. Results: [18F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. In vivo [18F]ASEM PET revealed an age-dependent increase uptake in the striatum and pallidum/nucleus basalis of Meynert in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. In vivo [18F]Florbetaben PET scanning detected Aβ accumulation at 18 m, and (S)-[18F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aβ plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aβ plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohi