Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, is characterized by the invariant cerebral accumulation of β-amyloid peptide. This event occurs early in the disease process. In humans, [18F]-Fluoro-2-deoxy-D-Glucose-Positron Emission Tomography ([18F]-FDG-PET) is largely used to follow-up in vivo cerebral glucose utilisation (CGU) and brain metabolism modifications associated to the AD pathology. Here, [18F]-FDG-PET was used to study age-related changes of CGU under resting conditions in 3, 6 and 12-month-old APPSweLon/PS1M146L, a mouse model of amyloidosis. We showed an age-dependent increase of glucose uptake in several brain regions of APP/PS1 mice but not in control animals and a higher [18F]-FDG uptake in the cortex and the hippocampus of 12-month-old APP/PS1 mice as compared to age-matched control mice. We then developed a method of 3D-microscopic autoradiography to evaluate glucose uptake at the level of amyloid plaques and showed an increased glucose uptake close to the plaques rather than in amyloid-free cerebral tissues. These data suggest a macroscopic and microscopic reorganisation of glucose uptake in relation to cerebral amyloidosis.

T1 and T2 magnetic resonance relaxation times have the potential to provide biomarkers of amyloid-beta deposition that could be helpful to the development of new therapies for Alzheimer's disease. Here, we measured T1 and T2 times as well as plaques and iron loads in APP/PS1 mice, which model brain amyloidosis, and control PS1 mice. Iron was mostly associated with amyloid deposits in APP/PS1 animals, while it was diffuse in the PS1 mice. T1 was negatively correlated with age in most structures in APP/PS1 animals. This may be related to the age-associated myelin loss described in APP/PS1 mice rather than to amyloid deposition. T2 in the subiculum of adult APP/PS1 animals was lower than in PS1 mice, which may be related to the very high amyloid and iron loads in this region. T2 in the subiculum could thus serve as an early marker of the amyloid pathology.

Amyloid-β peptide species accumulating in the brain of patients with Alzheimer's disease are assumed to have a neurotoxic action and hence to be key actors in the physiopathology of this neurodegenerative disease. We have studied a new mouse mutant (APPxPS1-Ki) line developing both early-onset brain amyloid-β deposition and, in contrast to most of transgenic models, subsequent neuronal loss. In 6-month-old mice, we observed cell layer atrophies in the hippocampus, together with a dramatic decrease in neurogenesis and a reduced brain blood perfusion as measured in vivo by magnetic resonance imaging. In these mice, neurological impairments and spatial hippocampal dependent memory deficits were also substantiated and worsened with aging. We described here a phenotype of APPxPS1-Ki mice that summarizes several neuroanatomical alterations and functional deficits evocative of the human pathology. Such a transgenic model that displays strong face validity might be highly beneficial to future research on AD physiopathogeny and therapeutics.