title: Early and progressive deficit of neuronal activity patterns in a model of local amyloid pathology in mouse prefrontal cortex.
abstract: Alzheimer's Disease (AD) is the most common form of dementia. The condition predominantly affects the cerebral cortex and hippocampus and is characterized by the spread of amyloid plaques and neurofibrillary tangles (NFTs). But soluble amyloid-β (Aβ) oligomers have also been identified to accumulate in the brains of AD patients and correlate with cognitive dysfunction more than the extent of plaque deposition. Here, we developed an adeno-associated viral vector expressing the human mutated amyloid precursor protein (AAV-hAPP). Intracranial injection of the AAV into the prefrontal cortex (PFC) allowed the induction of AD-like deficits in adult mice, thereby modelling human pathology. AAV-hAPP expression caused accumulation of Aβ oligomers, microglial activation, astrocytosis and the gradual formation of amyloid plaques and NFTs.In vivotwo-photon imaging revealed an increase in neuronal activity, a dysfunction characteristic of the pathology, already during the accumulation of soluble oligomers. Importantly, we found that Aβ disrupts the synchronous spontaneous activity of neurons in PFC that, as in humans, is characterized by ultraslow fluctuation patterns. Our work allowed us to track brain activity changes during disease progression and provides new insight into the early deficits of synchronous ongoing brain activity, the "default network", in the presence of Aβ peptide.
authors.affiliation: Institut Pasteur, Département de Neuroscience, Unité Neurobiologie intégrative des systèmes cholinergiques, 75724 Paris Cedex 15, ; CNRS, UMR 3571, Paris, France.
authors.forename: Fani
authors.initials: F
authors.lastname: Koukouli
authors.affiliation: Group for Neural Theory, Laboratoire de Neurosciences Cognitives, INSERM Unité 969, Département d'Études Cognitives, École Normale Supérieure, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Rooy
authors.affiliation: Institut Pasteur, Département de Neuroscience, Unité Neurobiologie intégrative des systèmes cholinergiques, 75724 Paris Cedex 15, ; CNRS, UMR 3571, Paris, France.
authors.forename: Uwe
authors.initials: U
authors.lastname: Maskos
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor
keywords: AAV; Alzheimer’s Disease; chronic two-photon imaging; human mutated APP; neuronal synchronicity