Abstract
Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, is currently conceptualized as a disease of synaptic failure. Synaptic impairments are robust within the AD brain and better correlate with dementia severity when compared with other pathological features of the disease. Nevertheless, the series of events that promote synaptic failure still remain under debate, as potential triggers such as β-amyloid (Aβ) can vary in size, configuration and cellular location, challenging data interpretation in causation studies. Here we present data obtained using adeno-associated viral (AAV) constructs that drive the expression of oligomeric Aβ either intra or extracellularly. We observed that expression of Aβ in both cellular compartments affect learning and memory, reduce the number of synapses and the expression of synaptic-related proteins, and disrupt chemical long-term potentiation (cLTP). Together, these findings indicate that during the progression AD the early accumulation of Aβ inside neurons is sufficient to promote morphological and functional cellular toxicity, a phenomenon that can be exacerbated by the buildup of Aβ in the brain parenchyma. Moreover, our AAV constructs represent a valuable tool in the investigation of the pathological properties of Aβ oligomers both in vivo and in vitro.
Highlights
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, afflicting approximately 5.5 million individuals in the USA and with a new case developing every 66 seconds[1]
associated viral (AAV) vectors encoding BRI-Aβ cDNAs, fusions between human Aβ peptides and the BRI protein, are able to promote high-level expression of Aβ peptide in the absence of amyloid precursor protein (APP) overexpression[19]
The findings of this study imply that intra- and extracellular Aβ accumulation mediated by AAV-gene transfer can promote deleterious effects on synaptic and cognitive functions
Summary
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, afflicting approximately 5.5 million individuals in the USA and with a new case developing every 66 seconds[1]. The early intraneuronal accumulation has been observed in transgenic rats McGill-R-Thy1-APP, which harbor the human APP751 transgene with the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter[12]. In these animals, the intraneuronal pathology was due to a mixture of APP, CTFs and a considerable amount of Aβ, leading to deleterious effects in the CNS before amyloid plaques develop. As plaques correlate poorly with AD-related dementia and little is known about the effects of intracellular Aβ on cognitive function, we asked whether these two distinct accumulation sites could have different effects on the development of pathology.
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