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

Abstract

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 [ 18 F]DPA-714 (TSPO, neuroinflammation), [ 18 F]Florbetaben (Aβ) and [ 18 F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[ 18 F]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)-[ 18 F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. Results: [ 18 F]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 [ 18 F]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 [ 18 F]Florbetaben PET scanning detected Aβ accumulation at 18 m, and (S)-[ 18 F]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) immunohistochemistry revealed a loss of neuronal staining at the Aβ plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both ge...

Positron Emission Tomography in Animal Models of Tauopathies

“…The (Ji et al, 2008(Ji et al, , 2021Maeda et al, 2011;Jacobs and Tavitian, 2012;Mirzaei et al, 2016;Ishikawa et al, 2018;Tournier et al, 2019Tournier et al, , 2020Barron et al, 2020;Takuwa et al, 2020;Chaney et al, 2021;Fairley et al, 2021;Leng and Edison, 2021;, and third generation [ 18 F]GE-180, etc. (Eckenweber et al, 2020;Chaney et al, 2021;Palleis et al, 2021).…”

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

“…Several studies have reported a reduced N-acetylaspartate/creatine ratio [ 148 , 149 ] and a lower glutamate level in APP/PS1 mice compared to wild-type mice [ 121 ]. Different metabolic profiles have also been demonstrated in animal models harboring both Aβ and tau pathologies, including 3 × Tg mice [ 153 ], 5 × FAD mice [ 152 ], APP/PS2/Tau mice [ 155 ], and TgF344 rats [ 146 ] ( Table 2 ). Lee et al demonstrated a 35% decrease in the availability of metabotropic glutamate receptor 5 measured by PET; a decrease in the levels of glutamate, N-acetylaspartate, and taurine; and an increase in the level of lactate by 1 H MRS in 5 × FAD mice compared to wild-type at 5 months-of-age [ 152 ].…”

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

“…Several studies have reported reduced N-acetylaspartate /creatine ratio [125] and [124], lower glutamate levels [123] in APP/PS1 mice compared to wild-type mice. In animal models haboring both Aβ and tau pathology, including 3×Tg [129], 5×FAD mice [130], APP/PS2/Tau mice [131] and TgF344 rat [132] (Table 2). Lee et al demonstrated a 35 % decrease in the availability of metabotropic glutamate receptor 5 measured by PET and a decrease in glutamate, N-acetylaspartate and taurine, levels and an increase in lactate level by 1 H MRS in 5×FAD mice compared to wild-type at 5 months-of-age [130].…”

“…5×FAD mice [135] MRS TgF344 rats [132] J20 mice [109] APP/PS1 mice [121][122][123][124][125][126] 5×FAD mice [130] 3×Tg mice [129] APPswe mice [127,128]. APP/PS2/Tau mice [131] TASTPM mice [131,167] APP/PS1 mice [105,125,164,168,236] McGill-R-Thy1-APP rats [162] mice [250,251] APP-Au mice [252] 3×Tg mice [93,165,253] APPswe mice [244] APP/PS1KI mice [166] APP/TTA mice [254] DKI APP/PS1 mice [184] 3×Tg mice [188] qMTI APPswe mice [178] DTI TgF344 rats [183] APPswe mice [175,178,186,255] PDAPP mice [176] App NL-G-F knock-in mice [72] APP/PS1 mice [123,171,179,187,189,256] APP23 ...…”