ApoE4 Impairs Dendritic Complexity In Adult Neurogenesis

The protein Apolipoprotein E (ApoE) plays a central role in proper development of adult-born neurons in the hippocampus, new research from a group at Columbia University indicates.

ApoE is one of the genes that regulate ongoing generation of neurons in the dentate gyrus of the hippocampus, a process known as adult neurogenesis. A variant of this gene called ApoE4 — present in 10 to 20 percent of the human population — is also strongly associated with the development of late-onset Alzheimer’s disease (AD).

Dr. Tzong-Shiue Yu, of Columbia’s Department of Pediatrics, and colleagues analysed adult-born neurons in the dentate gyrus of mice with the ApoE3 gene, ApoE4 gene, and with no ApoE gene. The ApoE3 allele, the most common variant in humans, is not associated with Alzheimer’s disease risk.

Reduced Complexity

Significant decreases in the complexity of dendritic branching and spine density in the ApoE-deficient mice were found compared with un-altered mice. In addition, ApoE4 mice compared to ApoE3 mice showed the same reduced complexity.

Type 1 NSPCs express nestin, ApoE, and GFAP, while mature granule cells make connections with astrocytes expressing ApoE and GFAP.

Type 1 NSPCs express nestin, ApoE, and GFAP, while mature granule cells make connections with astrocytes expressing ApoE and GFAP.
Credit: Tensaouti et al., eNeuro (2018)

Because Apolipoprotein E is known to regulate adult neurogenesis in the dentate gyrus of the hippocampus by directly affecting the proliferation of early neural progenitor cells, these results add to the growing evidence that cognitive deficits such as difficulty in learning new information and memory loss, are due to alterations in adult dentate gyrus neurogenesis.

These alterations are thought to play a key role in hippocampus-associated neurological conditions like traumatic brain injuries, epilepsy, major depressive disorder, schizophrenia, and Alzheimer’s disease. This study brings scientists a step closer to understanding how the strongest known genetic risk factor for AD contributes to memory impairment.

Apolipoprotein E

Lipoproteins are molecules consisting of fats and proteins. Apolipoprotein E is a fat-binding protein that which, in the brain, is secreted mostly by astrocytes and type 1 neural stem cells. It is involved in regulation of lipid transport mostly from astrocytes to neurons, blood–brain barrier maintenance, synaptogenesis, lipid intracellular homeostasis, and clearing away beta amyloid buildups.

A 2016 study from Gladstone Institutes researchers confirmed that apoE4 causes damage in human cells related to Alzheimer’s disease. The apoE4 protein differs from the apoE3 protein at only one point, but that single change is enough to alter its main structure and, thus, its function.

The researchers in this work created neurons from skin cells donated by Alzheimer’s patients with two copies of the apoE4 gene, as well as from healthy individuals who had two copies of the apoE3 gene.

The researchers confirmed that, in human neurons, the misshapen apoE4 protein cannot function properly and is broken down into disease-causing fragments in the cells. This process results in a number of problems commonly found in Alzheimer’s disease, including the accumulation of the protein tau and of amyloid peptides.

Notably, the presence of apoE4 does not change the production of amyloid beta in mouse neurons. But in human cells, scientists noticed apoE4 has a very clear effect on increasing amyloid beta production, which highlights the species difference in the way apoE4 controls amyloid beta metabolism.

ApoE4

People who inherit one copy of the e4 allele of the APOE gene have an increased chance of developing late-onset Alzheimer disease; those who inherit two copies of the allele are at even greater risk. The APOE e4 allele may also be linked with an earlier onset of memory loss and other symptoms.

It remains unclear how the APOE e4 allele is related to the risk of Alzheimer disease. However, previous research has shown that this allele is associated with an increased number of protein clumps, called amyloid plaques, in the brain tissue of affected people. A buildup of toxic amyloid beta peptide and amyloid plaques may lead to the death of neurons and the progressive signs and symptoms of this disorder.

Decrease in the proportion of complex and increase of less complex adult-born granule cells in ApoE-deficient and ApoE4 mice.

Decrease in the proportion of complex and increase of less complex adult-born granule cells in ApoE-deficient and ApoE4 mice.
Credit: Tensaouti et al., eNeuro (2018)

It is important to note that people with the APOE e4 allele inherit an increased risk of developing Alzheimer disease, not the disease itself. Not all people with Alzheimer disease have the APOE e4 allele, and, although 40-65% of AD patients have at least one copy of the ε4 allele, not all people who have this allele will develop the disease.

Yacine Tensaouti, Elizabeth P. Stephanz, Tzong-Shiue Yu, Steven G. Kernie
ApoE Regulates the Development of Adult Newborn Hippocampal Neurons
eNeuro 30 July 2018, 5 (4) ENEURO.0155-18.2018; DOI: 10.1523/ENEURO.0155-18.2018

Top Image: ApoE-expressing astrocytes (green) interacting with tdTomato-expressing dendrites (red) from adult newborn hippocampal neurons. Credit: Tensaouti et al., eNeuro (2018)