Active meprin-β elevated in Alzheimer's brain and cerebrospinal fluid

An overlooked enzyme in a well-studied disease

Alzheimer's disease is defined in part by the accumulation of beta-amyloid in the brain, a peptide released when amyloid precursor protein (APP) is processed by a series of enzymes. Among them are the β-secretases, and for years one member of that group — BACE1 — has absorbed the overwhelming share of research attention. A team in Spain now reports that a different protein, meprin-β, is present in an elevated and active form in both the brain and the cerebrospinal fluid of people with Alzheimer's disease.

The findings come from the Altered Molecular Mechanism in Alzheimer's Disease and Dementia laboratory at the Institute for Neurosciences (IN), a joint center of Miguel Hernández University of Elche (UMH) and the Spanish National Research Council (CSIC). The laboratory is led by Javier Sáez Valero, who is also the principal investigator of the study, which was published in Alzheimer's Research & Therapy.

"Until now, much of the attention has focused on BACE1 as a relevant β-secretase in Alzheimer's disease," Sáez Valero said. "Our work shows that there is another protein, meprin-β, whose active form is increased in the brain and cerebrospinal fluid of people with this disease."

The authors present the result as new evidence of a possible relationship between meprin-β and processes associated with beta-amyloid, one of the hallmarks of Alzheimer's. That framing is deliberately measured: the work identifies an association that merits follow-up, not a proven mechanism of disease.

Active and inactive forms are not interchangeable

Meprin-β is an enzyme that can exist in more than one state, and the researchers treated those states as separate questions rather than as a single measurement. They analyzed the immature, inactive form of the protein independently from its mature, active counterpart.

• Immature meprin-β: the form that has not yet acquired its full enzymatic capability.
• Mature meprin-β: the active form, capable of cleaving target proteins.

That separation is more than a technical detail. Only the mature version of the enzyme can carry out the kind of cleavage activity that produces beta-amyloid from APP. If a study were to lump the two forms together, a genuine shift in enzymatic activity could be diluted or hidden by the pool of inactive protein, making the result harder to interpret. By measuring the forms independently, the team was able to report specifically that the active species is the one that rises.

Braak staging ties the signal to disease progression

To trace what happens as Alzheimer's advances, the researchers studied samples of the frontal cortex taken from people at different stages of the disease and compared them with samples from people who did not have Alzheimer's disease. The tissue was classified according to Braak stages, the scale widely used to describe how far pathology has spread through the brain.

The active form of meprin-β increased in the more advanced stages of the disease, corresponding to higher Braak stages. That increase was not observed in the early stages. The pattern points to a protein change that becomes more pronounced as the disease progresses, rather than a constant feature present from the outset.

Elevated levels of the protein were also found in cerebrospinal fluid, the fluid that surrounds the brain and spinal cord. Finding a signal in both brain tissue and fluid matters because cerebrospinal fluid is far more accessible than brain tissue in living patients.

Imagery accompanying the research includes cell cultures of induced pluripotent stem cells (iPSCs), with neurons shown in green and astrocytes in red, credited to Carlos Avilés Granados.

Why a second β-secretase is worth tracking

Beta-amyloid does not appear spontaneously. It is the product of a processing chain that begins with APP, and the enzymes that cut APP at particular points determine how much of the peptide is generated. BACE1 has long been treated as the principal β-secretase in that chain. The new work adds weight to the idea that other enzymes, meprin-β among them, can serve a similar function and may be relevant to the biology of the disease.

Enzymes that act on APP are attractive to study because they sit upstream of the peptide at the center of so much Alzheimer's research. If more than one enzyme can generate beta-amyloid, then mapping the full cast of actors becomes part of understanding the disease itself — even before any of them is considered as a possible target.

What the study does and does not establish is worth stating plainly:

• It reports that the active form of meprin-β is elevated in the brain at more advanced Braak stages.
• It reports elevated levels of the protein in cerebrospinal fluid from people with Alzheimer's disease.
• It offers evidence of a possible relationship with beta-amyloid-related processes, as the authors describe it.
• It does not show that meprin-β drives the disease, nor that reducing its activity would alter its course.

Questions that remain open

The results raise as many questions as they answer, and the team's own framing acknowledges that the underlying biology is unresolved. Several lines of inquiry follow naturally from the data:

• Does the rise in active meprin-β precede, accompany, or follow the accumulation of beta-amyloid?
• How does meprin-β activity compare with BACE1 activity across the same stages of disease?
• Is the increase detected in cerebrospinal fluid consistent enough to be measured reliably in patients?
• Do the immature and mature forms behave differently in brain regions beyond the frontal cortex?

The bottom line

The study adds a protein to the short list of enzymes worth watching in Alzheimer's disease. Meprin-β, long in the shadow of BACE1, appears in an elevated active form in the brains and cerebrospinal fluid of people with the condition, and the increase tracks with more advanced Braak stages in frontal cortex samples. The authors stop short of claiming a causal role, describing the findings instead as evidence of a possible relationship with beta-amyloid-associated processes.

For a field that has spent years focused on a single β-secretase, that is a meaningful addition to the map — and an invitation to look more closely at what else is cutting APP in the Alzheimer's brain.

This article is based on reporting by Medical Xpress. Read the original article.