HEBP1 A Potential Early Marker of Alzheimer’s Disease

by Dr Khor Ing Wei
Senior Manager, Dean’s Office

A protein in the body helps excessive amounts of free heme to kill neurons in early-stage Alzheimer’s disease (AD), and may be a promising early marker of AD.

As AD markers go, abnormal aggregates of the amyloid-beta (Aß) and Tau proteins are the obvious indicators. However, they do not fully correlate with the progress of cognitive decline in AD. Aß and Tau aggregates also tend to come into play later in the AD disease process, when symptoms of the disease may already be apparent (unsurprisingly, they were discovered in postmortem brains of people who suffered from AD). By this point, the initial biological events that pave the way for disease development have already occurred. Having a marker of AD that shows changes at an early stage would help doctors to diagnose AD earlier (even before symptoms occur), and sheds some light on what happens early in the disease process.

Promising early marker of Alzheimer’s disease

In August 2019, Assistant Professor John Chua Jia En of the Department of Physiology at NUS Medicine, his former PhD student Dr Oleksandr Yagensky (now at the Max Planck Institute for Biophysical Chemistry in Goettingen, Germany), and collaborators published an article about the potential early marker of AD, heme-binding protein 1 (Hebp1), in the prestigious open-access journal eLife.

The team of researchers presented strong evidence to support a role for Hebp1 in the development and progression of AD, encompassing findings in both preclinical models and postmortem brains of AD patients. By analysing the data for many proteins in the brain, the researchers identified the Hebp1 protein as showing the greatest change in concentration in AD vs control brains in a preclinical model of AD, at all time points. These time points were at 2 months (before symptoms appeared), 6 months (first behavioural changes), 12 months (first appearance of abnormal Aß proteins, a hallmark of AD) and 18 months (abnormal Aß and Tau proteins, another sign of AD).

Interestingly, when the researchers looked at Hebp1 levels in the postmortem brains of AD patients, they discovered that levels increased the most (vs controls) in rapidly progressing AD cases, in which the period from diagnosis to death was four years or less. This provocative finding suggested that Hebp1, besides being active early in AD, might also be involved in disease progression.

The role of Hebp1

Next, the team wanted to find out how Hebp1 influenced the development of AD. From previous work, the researchers knew that Hebp1 was likely to be involved in transporting the compound heme from the mitochondria to the cytosol of the cell. Although heme is needed for many biological processes, excessive levels of free heme can kill cells.

The panels in Figure 1 show the killing of neurons in response to hemin (free heme), abnormal Aß protein (Aß42), and a combination of both. Every yellow spot indicates a dying neuron. Panels 1 and 2 show that free heme or abnormal Aß protein kill more normal neurons (more yellow spots) than neurons that are missing the Hebp1 protein. A combination of free heme and abnormal Aß protein (Panel 3) kills more neurons than each toxin alone (Panels 1 and 2). Again, the combination is more deadly in normal neurons than in neurons lacking Hebp1. These results indicate that Hebp1 is involved in the killing mechanism of free heme and abnormal Aß protein.

Asst Prof Chua and colleagues showed that excessive levels of heme damaged the mitochondrial membrane, causing Hebp1 to be released from the mitochondria in neurons. They postulated that the liberated Hebp1 sets off a series of events that culminates in the death of neurons, which in turn contributes to the cognitive decline in AD.

Interestingly, the researchers found that Hebp1 was also involved in the destruction of neurons induced by abnormal Aß protein. The combination of excessive heme and abnormal Aß protein induced twice the rate of neuronal death, compared with that caused by abnormal Aß alone. Neurons that lacked Hebp1 showed much less neuronal death when exposed to excessive heme or abnormal Aß protein, or to a combination of both toxins. These findings, illustrated in Figure 1, point to the potential use of Hebp1 as an early marker for AD and a target for novel AD therapies.

What this could mean for people with AD

Asst Prof Chua hopes that this discovery could eventually contribute to earlier diagnoses of AD and improved management of the disease. He adds, “The possibility to slow down or even reverse early neuronal damage would be immensely helpful in improving the quality of life of patients with AD.”