Release of ApoE4 Fragments and Increased Tau Protein Contribute to Risk of Alzheimer's Disease

Results of a recent study suggested that the interaction between apolipoprotein E4 (ApoE4) and the enzyme high-temperature requirement serine peptidase A1 (HtrA1) was linked in some fashion to the development of late onset Alzheimer's disease (AD).

HtrA1 is a secreted enzyme that has been proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Since this enzyme is found in the nervous system, investigators at the Salk Institute for Biological Studies (La Jolla, CA, USA) decided to examine its relationship to ApoE4, which has been demonstrated to be an Alzheimer's disease risk factor.


ApoE belongs to a large class of proteins that solubilize lipids for physiological transport. Humans have three different APOE alleles, APOE2, APOE3, and APOE4, and genetic studies identified ApoE4 as the strongest genetic risk factor for Alzheimer’s disease (AD). Individuals who are homozygous for ApoE4 (ApoE4/E4) are an order of magnitude more likely to develop late-onset AD than ApoE3/E3 carriers. Several differences between ApoE3 and ApoE4 may contribute to AD including the observation that ApoE4 is degraded to a greater extent than ApoE3 in the human brain.

The investigators reported in the August 2016 issue of the Journal of the American Chemical Society that experiments with HtrA1 demonstrated that HtrA1 was an allele-selective ApoE-degrading enzyme that degraded ApoE4 more quickly than ApoE3. This activity was specific to HtrA1, as similar assays with HtrA2 showed minimal ApoE4 proteolysis and trypsin had no preference between ApoE4 and ApoE3. This result suggested that ApoE4/E4 individuals would have less ApoE overall in their brain cells and more potentially toxic ApoE4 breakdown products.

HtrA1 was also reported to cleave the tau protein (Tau) and the amyloid protein precursor (APP) to hinder the formation of toxic amyloid deposits associated with AD. Competition assays with ApoE4, ApoE3, and Tau revealed that ApoE4 inhibited Tau degradation by HtrA1, thereby increasing levels of Tau protein in the brain and the risk of AD.

“ApoE4 is the most predictive genetic change for late onset Alzheimer’s, but no one has really understood what is going on at the molecular level,” said senior author Dr. Alan Saghatelian, professor of peptide biology at the Salk Institute for Biological Studies. “There has been an idea tossed around that ApoE4 breakdown products could be toxic. Now, knowing the enzyme that breaks it down, we have a way to actually test this idea. People have thought about tau or amyloid beta as things that cause Alzheimer’s, but this suggests that we need to think more globally about proteins that could be impacting tau or amyloid through biochemical pathways. The big picture here is that we have found a very different way of thinking about how the proteins in Alzheimer’s disease might be regulated.”

Related Links:
Salk Institute for Biological Studies