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 vivo two-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.
Highlights
Alzheimer’s Disease (AD) is a devastating neurodegenerative condition that greatly impacts society, primarily affecting the elderly population, and will become an enormous burden as the population ages [1]
To more effectively study AD pathology, it is necessary to dissect the pathological mechanisms using in vivo models and recording methods identifying the functional changes
The associated virus (AAV) was made to express mutant human APP harboring the Swedish, London and Austrian mutations that are associated with early onset of AD
Summary
Alzheimer’s Disease (AD) is a devastating neurodegenerative condition that greatly impacts society, primarily affecting the elderly population, and will become an enormous burden as the population ages [1]. In the broad category of dementia, AD amounts to 70% of all cases and thereby is the most common form of dementia [2]. Various transgenic mouse models of AD harboring mutations in these genes have been established to decipher the disease mechanism. A significant advance in the field came from the development of transgenic rodent models that exhibit tau pathology [5,6]. The results from these models have unraveled specific components of the disease pathology and given indications for developing potential therapies, there is no transgenic model that replicates the broad spectrum of AD pathology. In transgenic mice that express human familial AD mutations, the gene is expressed throughout the brain, making it impossible to study disease induced changes in specific brain regions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
