Reversing Learning and Memory Deficits in Alzheimer’s Disease

The existence of amyloid beta plaques in the brains of Alzheimer’s disease patients led to the idea that the plaques may be the cause of the disease. Research now suggests that it’s the soluble form of amyloid beta that may contributes to learning and memory deficits in Alzheimer’s disease. We all have this form of amyloid beta in our brains but recent research shows that clearance of amyloid beta is significantly slower in Alzheimer’s disease patients than in cognitively normal individuals (see blog post “Decreased Clearance of Amyloid Beta from the Central Nervous System in Alzheimer’s Disease“).

Soluble amyloid beta correlates with inhibited NMDA receptor dependent long-term potentiation (LTP). The NMDA receptor is a type of glutamate receptor that plays a lead role in LTP, which is thought to underlie memory formation through the strengthening of synapses. Those with Alzheimer’s disease have reduced levels of NMDA receptor components. Alzheimer’s disease patients also have significantly less Ephrin type-B receptor 2 (EphB2) in their hippocampus. It’s known that EphB2 regulates NMDA receptor trafficking and function and mice lacking EphB2 have impaired NMDA receptor dependent LTP and memory deficits.

In a recent report (“Reversing EphB2 depletion rescues cognitive functions in Alzheimer model” published January 6, 2011 in Nature) the authors hypothesized that EphB2 depletion in Alzheimer’s disease is caused by amyloid beta oligomers and that reductions in EphB2 contribute to amyloid beta induced deficits in synaptic plasticity and cognitive functions. By carrying out experiments using a wide range of techniques, from manipulating molecules and genes to testing cognitive abilities, the team was able to confirm their hypothesis and they were even able to reverse the learning and memory effects of EphB2 depletion.

Specifically, they showed that:

• Amyloid beta binds to EphB2 and the binding leads to increased degradation of EphB2.
• EphB2 depletion impairs LTP and reduces synaptic strength.
• Increasing EphB2 in the hippocampus reversed the NMDA receptor mediated decrease in synaptic strength and it reversed learning and memory deficits as measured by both spatial and non-spatial learning and memory tasks.

The experiments were done in mice genetically manipulated to have Alzheimer’s disease like symptoms. It’ll be important to show that similar mechanisms are at work in the human. Also, a recent article attributed changes in NMDA receptor function to tau (see blog post “Synaptic Dysfunction without Neurodegeneration“). Are these separate and unrelated mechanisms or could they be connected somehow?

Other related blog posts:

Alzheimer’s Disease and the New Age-Based Hypothesis

Decreased Clearance of Amyloid Beta from the Central Nervous System in Alzheimer’s Disease

Synaptic Dysfunction without Neurodegeneration