ABSTRACT
Neuronal activity patterns are disrupted in neurodegenerative disorders, including Alzheimer's disease (AD). One example is disruption of corticothalamic slow oscillations responsible for sleep-dependent memory consolidation. Slow waves are periodic oscillations in neuronal activity occurring at frequencies of <1 Hz. The power, but not the frequency of slow oscillations is altered in a mouse model of AD. Optogenetic rescue of slow oscillations by increasing activity in cortical pyramidal neurons at the frequency of slow waves restores slow wave power, halts deposition of amyloid plaques and prevents neuronal calcium dysregulation. Here we determined whether driving this circuit at an increased rate would exacerbate the amyloid-dependent calcium dyshomeostasis in transgenic mice. Doubling the frequency of slow waves for one month with optogenetics resulted in increased amyloid beta - dependent disruptions in neuronal calcium homeostasis and loss of synaptic spines. Therefore, while restoration of physiological circuit dynamics is sufficient to abrogate the progression of Alzheimer's disease pathology and should be considered an avenue for clinical treatment of AD patients with sleep disorders, pathophysiological stimulation of neuronal circuits leads to activity - dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction.
Subject(s)
Alzheimer Disease/etiology , Alzheimer Disease/pathology , Disease Susceptibility , Alzheimer Disease/metabolism , Amyloid/genetics , Amyloid/metabolism , Amyloid beta-Peptides/metabolism , Animals , Calcium/metabolism , Disease Models, Animal , Disease Progression , Image Processing, Computer-Assisted , Mice , Mice, Transgenic , Microscopy, Fluorescence, Multiphoton , Molecular Imaging , Neurons/metabolism , Neurons/pathology , Neurotransmitter Agents/metabolism , Plaque, Amyloid/etiology , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Synaptic TransmissionABSTRACT
Soluble amyloid ß oligomers (AßOs) are widely recognized neurotoxins that trigger aberrant signaling in specific subsets of neurons, leading to accumulated neuronal damage and memory disorders in Alzheimer's disease (AD). One of the profound downstream consequences of AßO-triggered events is dysregulation of cytosolic calcium concentration ([Ca2+]i), which has been implicated in synaptic failure, cytoskeletal abnormalities, and eventually neuronal death. We have developed an in vitro/in vivo drug screening assay to evaluate putative AßO-blocking candidates by measuring AßO-induced real-time changes in [Ca2+]i. Our screening assay demonstrated that the anti-AßO monoclonal antibody ACU3B3 exhibits potent blocking capability against a broad size range of AßOs. We showed that picomolar concentrations of AßOs were capable of increasing [Ca2+]i in primary neuronal cultures, an effect prevented by ACU3B3. Topical application of 5 nM AßOs onto exposed cortical surfaces also elicited significant calcium elevations in vivo, which was completely abolished by pre-treatment of the brain with 1 ng/mL (6.67 pM) ACU3B3. Our results provide strong support for the utility of this functional screening assay in identifying and confirming the efficacy of AßO-blocking drug candidates such as the human homolog of ACU3B3, which may emerge as the first experimental AD therapeutic to validate the amyloid oligomer hypothesis.
