2023 Alzheimer's Association Research Fellowship (AARF)
Cognitive Failure in AD: NPTX2 Dysregulation by ACh- and Aß-Mechanisms
Can loss of function in a gene linked to brain cell communication promote brain cell damage in early Alzheimer’s?
Seung-Eon Roh, Ph.D.
Johns Hopkins University School of Medicine
Baltimore, MD - United States
Background
Alzheimer’s is a progressive disorder, and because of this, scientists have been studying how the disease develops at its earliest stages – before memory loss and other cognitive symptoms become evident. One early change in Alzheimer’s involves synapses, the specialized structures nerve cells use to communicate with each other. Recent studies have found that a synaptic gene called neuronal pentraxins 2, or NPTX2, becomes dysfunctional in early Alzheimer’s. NPTX2 is generated by cells called parvalbumin interneurons (PVs), and it helps regulate the activity of other nerve cells known as pyramidal neurons, which are important for many cognitive abilities, such as writing, speaking, and advanced thinking. Loss of NPTX2 function may cause “excitotoxicity” in pyramidal neurons, in which the cells become overstimulated and damaged – a process that can lead to dementia-related cognitive decline. Scientists, however, are uncertain exactly how this synaptic gene becomes dysfunctional and promotes excitotoxicity and brain cell loss.
In initial studies, Dr. Seung-Eon Roh and colleagues found that NPTX2-related brain cell damage may be linked to both beta-amyloid (a protein that accumulates into hallmark plaques in Alzheimer’s) and cholinergic neurons (nerve cells that use a chemical messenger called acetylcholine, or ACh, to communicate with one another). The researchers observed that cholinergic neurons may play a role in regulating NPTX2 activity, especially during sleep. However, in early Alzheimer’s, beta-amyloid accumulation can disrupt this regulating function, which may lead to a loss of NPTX2 activity, pyramidal neuron damage, and cognitive decline.
Research Plan
Dr. Roh and colleagues will now conduct a larger study to verify and expand on their earlier results. This effort will utilize mice, some of which were engineered to develop beta-amyloid in their brains. First, the researchers will clarify how cholinergic neurons regulate the activity of NPTX2 in cognitively unimpaired mice. Second, using mice that express beta-amyloid, they will examine in more detail how amyloid clumping disrupts cholinergic regulation of NPXT2 and promotes brain cell damage and cognitive loss.
Impact
The results of this study will help clarify the role of synaptic dysfunction in early Alzheimer’s. They could also identify NPXT2 as a novel target for future dementia therapies.