Effects Of Modulating PV Interneurons On Aβ-induced Neuropathology In An Animal Model Of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease. The pathological hallmarks of AD include extracellular amyloid plaques composed mainly of amyloid β (Aβ), intracellular neurofibrillary tangles composed mainly of tau, synaptic dysfunction and massive neuronal loss. Accumulating of evidence indicates that abnormal accumulation of Aβ in the brain is the major initial factor for AD. Unfortunately, however, the underlying mechanisms remain elusive. Recent studies found that Aβ overexpression caused impairment of GABAergic interneurons, especially interneuons expressing parvalbumin (PV), which resulted in aberrant activity of neural circuits or neural networks. However, it is not clear so far whether Aβ-induced neuronal deficits could be affected by stimulating PV-expressing neurons directly. In the present study, we expressed channelrhodopsin-2(ChR2), a light-sensitive ion channel, specifically in PV neurons of hAPP-J20mice by using the Cre-loxp strategy, and then stimulated PV neurons in the cortex by optogenetics. We then checked the amyloid plaque load by3D6staining and neural network activity by electroencephalogram (EEG) in hAPP-J20mice. We found that activating PV neurons in the cortex decreased the amyloid plaque load in the hippocampus. Abnormal expression of neuropeptide Y (NPY) in the hippocampus of hAPP-J20mice was also decreased after PV neuron activation. EEG recordings showed that the power of gamma rhythm in dentate gyrus (DG) on the side with laser illumination decreased, but not on the non-stimulated side or in the cortex. Our data indicated that direct activation of PV neurons in the cortex decreased partially the Aβ-induced neuronal deficits in hAPP-J20mice.