Study shows how Alzheimer’s risk gene disrupts memory replay.


It is known that one of the earliest sites of Alzheimer’s disease pathology is the hippocampus, a brain structure critical for the learning and memory processes that falter early in Alzheimer’s disease.  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.  ApoE4 protein is the major genetic risk factor for Alzheimer’s disease, however, the mechanism by which it causes cognitive decline and disrupts hippocampal memory processes is unclear.  Now, a study from researchers at the Gladstone Institutes shows that the apoE4 protein changes the activity of neurons in the hippocampus.  The team state that in this region, apoE4 decreases two types of brain activity that are important for memory formation, namely, sharp wave ripples and coincident slow gamma activity.  The opensource study is published in the journal Neuron.

Previous studies show that when a person experiences something new, cells in the hippocampus fire in a particular order. Later, these same cells fire repeatedly in the same order to replay the event, which helps consolidate the memory so the person doesn’t forget it.  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.  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.  The current study shows that progressive decline of interneuron-enabled slow gamma activity during sharp wave ripples critically contributes to apoE4-mediated learning and memory impairments.

The current study 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.  Results show that the mice exhibited normal slow gamma activity despite having fewer ripples. Data findings show that 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.

The team surmise that their findings suggest disrupted slow gamma activity during ripples is a major consequence of apoE4 expression that likely impairs memory consolidation.  For the future, the researchers state that with this knowledge, the global medical community can now work toward correcting or restoring slow gamma activity in the hippocampus to prevent or alleviate memory loss in Alzheimer’s disease.

Source: Gladstone Institutes

 

LFP Recording of Hippocampal Network Activity in ApoE3-KI and ApoE4-KI Mice.  Representative Nissl staining of brain sections after electrolytic lesioning indicates probe placement, shown in sequential coronal sections.  Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples.  Huang et al 2016.

LFP Recording of Hippocampal Network Activity in ApoE3-KI and ApoE4-KI Mice. Representative Nissl staining of brain sections after electrolytic lesioning
indicates probe placement, shown in sequential coronal sections. Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples. Huang et al 2016.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s