Entorhinal Cortical Deep Brain Stimulation Rescues Memory Deficits in Both Young and Old Mice Genetically Engineered to Model Alzheimer's Disease

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 42; no. 13; pp. 2493 - 2503
• Main Authors: Xia, Frances, Yiu, Adelaide, Stone, Scellig S D, Oh, Soojin, Lozano, Andres M, Josselyn, Sheena A, Frankland, Paul W
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2017
• Subjects: Age; Aging - physiology; Aging - psychology; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer Disease - psychology; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animal memory; Animals; Brain; Cognitive ability; Cortex (entorhinal); Deep Brain Stimulation; Disease Models, Animal; Drug development; Entorhinal Cortex - pathology; Entorhinal Cortex - physiopathology; Fear; Fear - physiology; Female; Genetic engineering; Hippocampus; Humans; Male; Memory - physiology; Memory Disorders - etiology; Memory Disorders - pathology; Memory Disorders - physiopathology; Memory Disorders - therapy; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative diseases; Original; Plaque, Amyloid - pathology; Plaque, Amyloid - physiopathology; Plaque, Amyloid - prevention & control; Rodents; Spatial Learning - physiology; Spatial memory; Stimulation; Transgenic mice
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2017.100

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Deep brain stimulation (DBS) has been used to treat a variety of brain disorders and shows promise in alleviating cognitive symptoms in some AD patients (Laxton et al, 2010). We previously showed that DBS of the entorhinal cortex (EC) enhances spatial memory formation in normal (wild-type) mice (Stone et al, 2011). Here we tested the effects of EC-DBS on the progressive cognitive deficits in a genetically-based mouse model of AD. TgCRND8 (Tg) transgenic mice express human amyloid precursor protein harboring the Swedish and Indiana familial AD mutations. These mice exhibit age-related increases in Aβ production, plaque deposition, as well as contextual fear and spatial memory impairments. Here, we found EC stimulation in young mice (6 weeks old) rescued the early contextual fear and spatial memory deficits and decreased subsequent plaque load in Tg mice. Moreover, stimulation in older mice (6 months old) was also sufficient to rescue the memory deficits in Tg mice. The memory enhancement induced by DBS emerged gradually (over the course of weeks) and was both persistent and specific to hippocampal-based memories. These results provide further support for the development of novel therapeutics aimed to resolve the cognitive decline and memory impairment in AD using DBS of hippocampal afferents.