Alzheimer’s Gene Impairs Memory by Disrupting Brain’s ‘Playback System’

Abnormal brain activity hinders memory replay in the apoE4 mouse model of Alzheimer’s disease.

Scientists at the Gladstone Institutes have discovered how the major genetic risk factor for Alzheimer’s disease causes memory impairment. A specific type of brain activity important for memory replay is disrupted in mice with the E4 version of the apolipoprotein E (apoE4) gene, which may interfere with memory formation.

The apoE4 gene creates a protein of the same name that markedly increases a person’s risk for Alzheimer’s disease and occurs in 65%-80% of people with Alzheimer’s disease. In the new research, published in Neuron, the scientists found that the apoE4 protein changes the activity of neurons in the hippocampus — an important memory center in the brain that is severely affected by Alzheimer’s disease. In this region, apoE4 decreases two types of brain activity that are important for memory formation: sharp wave ripples (ripples) and coincident slow gamma activity. During the ripples, prior experiences are replayed numerous times to help preserve the memory of them, and the slow gamma activity that occurs during the ripples helps to ensure that the replay of those memories is accurate.

“When we experience something new, cells in the hippocampus fire in a particular order. Later, these same cells fire over and over again in the same order to replay the event, which helps consolidate the memory so we don’t forget it,” explained first author Anna Gillespie, PhD, a former graduate student in the Huang lab at Gladstone. “Slow gamma activity that occurs during the ripples organizes the firing of these cells. If this activity is disrupted, the playback will be disorganized, compromising the memory.”

Image shows brain slices.
Mice with apoE4 had fewer ripples than mice with the normal apoE3 protein, and they had less slow gamma activity during the ripples. Based on these results, the scientists questioned whether these differences in activity affected the ability to form and replay memories. Image is for illustrative purposes only. Image is credited to Andrews-Zwiling Y. et al./Journal of Neuroscience, and is adapted from the Gladstone Institute video.

Mice with apoE4 had fewer ripples than mice with the normal apoE3 protein, and they had less slow gamma activity during the ripples. Based on these results, the scientists questioned whether these differences in activity affected the ability to form and replay memories.

To answer this, the researchers tested mice that expressed apoE4 in all cells except inhibitory neurons in the hippocampus. From earlier research, the scientists knew that these mice showed no signs of inhibitory neuron death in the hippocampus, and their ability to learn and form memories was not impaired. In the current study, the mice showed normal slow gamma activity despite having fewer ripples. Thus, slow gamma activity–the coordination of cell firing during playback — appears to be a critical factor in memory consolidation, rather than the number of replay events from the ripples.


In a study published in the journal Neuron, scientists at the Gladstone Institutes have discovered how the major genetic risk factor for Alzheimer’s disease, the apoE4 gene, causes memory impairment. A specific type of brain activity important for memory replay is disrupted in apoE4 mice, which may interfere with memory formation.

“Our research suggests that disrupted slow gamma activity during ripples is a major consequence of apoE4 expression that likely impairs memory consolidation,” said senior author Yadong Huang, MD, PhD, a senior investigator at Gladstone. “With this knowledge, we can now work toward correcting or restoring slow gamma activity in the hippocampus to prevent or alleviate memory loss in Alzheimer’s disease.”

About this Genetics research

Other Gladstone scientists on the study include Emily Jones, Yuan-Hung Lin, Seo Yeon Yoon, Leslie Tong, Philip Nova, and Jessie Carr. Loren Frank and other researchers from the University of California, San Francisco also contributed to the research.

Funding: Funding provided by Achievement Rewards for College Scientists Foundation, Larry L. Hillblom Foundation, NIH/National Institute on Aging, McKnight Foundation, S.D. Bechtel, Jr. Foundation, Hellman Foundation.

Source: Gladstone Institute
Image Credit: The image is credited to Andrews-Zwiling Y. et al./Journal of Neuroscience, and is adapted from the Gladstone Institute video.
Video Source: The video is credited to Gladstone Institutes.
Original Research: Abstract for “Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples” by Anna K. Gillespie, Emily A. Jones, Yuan-Hung Lin, Mattias P. Karlsson, Kenneth Kay, Seo Yeon Yoon, Leslie M. Tong, Philip Nova, Jessie S. Carr, Loren M. Frank, and Yadong Huang in Neuron. Published online May 5 2016 doi:10.1016/j.neuron.2016.04.009


Abstract

Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples

Highlights

•ApoE4-KI mice show age-dependent attenuation of slow gamma activity during SWRs
•ApoE4-KI mice, both young and aged, have fewer SWRs than apoE3-KI mice
•ApoE4-induced slow gamma impairment, not SWR abundance, is interneuron dependent
•Progressive slow gamma dysfunction during SWRs may contribute to cognitive decline

Summary
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional apoE4-KI phenotypes involving sharp-wave ripples (SWRs), hippocampal network events critical for memory processes. Aged apoE4-KI mice had fewer SWRs than apoE3-KI mice and significantly reduced slow gamma activity during SWRs. Elimination of apoE4 in GABAergic interneurons, which prevents learning and memory impairments, rescued SWR-associated slow gamma activity but not SWR abundance in aged mice. SWR abundance was reduced similarly in young and aged apoE4-KI mice; however, the full SWR-associated slow gamma deficit emerged only in aged apoE4-KI mice. These results suggest that progressive decline of interneuron-enabled slow gamma activity during SWRs critically contributes to apoE4-mediated learning and memory impairments.

“Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples” by Anna K. Gillespie, Emily A. Jones, Yuan-Hung Lin, Mattias P. Karlsson, Kenneth Kay, Seo Yeon Yoon, Leslie M. Tong, Philip Nova, Jessie S. Carr, Loren M. Frank, and Yadong Huang in Neuron. Published online May 5 2016 doi:10.1016/j.neuron.2016.04.009

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