Multimodal Imaging Reveals Heterogeneity in Amyloid Plaques

Alzheimer's disease (AD), which affects millions of people globally, is still one of the most difficult and common neurodegenerative conditions. Researchers under the direction of Professor Lucía Chávez Gutiérrez (VIB-KU Leuven), Professor William Mobley (UCSD, USA), and Carsten Hopf (CeMOS, Mannheim, Germany) recently published two studies that provide important new insights into the role of toxic protein fragments and plaque composition in AD.

Amyloid plaques are a prominent characteristic of the brains of people with Alzheimer's disease (AD). These plaques are made up of misfolded β-amyloid fragments (Aβ) that accumulate in clumps within the neurons. The Amyloid Precursor Protein (APP), which is found in brain cell membranes, is broken down into these fragments.

The brain breaks down and eliminates old APP molecules while continuously producing new ones. Enzymatic cleavage is used in this “waste disposal” process, and the enzyme responsible for the well-known poisonous Aβ peptides in AD is gamma-secretase.

At the VIB-KU Leuven Center for Brain & Disease Research, Prof. Lucía Chávez Gutiérrez's lab is dedicated to comprehending how protein cleavage functions in the molecular processes that underlie AD.

Her team has recently published two new studies that significantly advance the knowledge of the function of gamma-secretase inhibition and the significance of amyloid plaque makeup.

Hacking the Enzymatic Scissor

The first study, published in eLife, reveals a novel mechanism in which Aβ42, or Aβ—fragments with a length of 42 amino acids, may play a role in neurodegeneration and neuronal physiology. According to the study, Aβ42 can obstruct gamma-secretase activity, which is crucial for cellular viability.

Besides the breakdown of APP, gamma-secretase is also crucial for normal cell signaling. We discovered that Aβ42 binds to and inhibits gamma-secretase, leading to a build-up of other toxic cellular materials which may ultimately cause neuronal death. Our findings suggest that Aβ42 can worsen Alzheimer's disease not just by accumulating in plaques but also by directly interfering with cellular processes.”

Dr. Katarzyna Zoltowska, Study First Author, VIB-KU Leuven

Dr. Utpal Das (UCSD, USA), who also contributed to the study, added, “The researchers can now explore ways to prevent Aβ42 from inhibiting gamma-secretase, thereby potentially restoring normal cellular communication.”

Diversity Within Plaques

Plaque heterogeneity is the subject of the second study, which was conducted in cooperation between VIB-KU Leuven and the Center for Mass Spectrometry and Optical Spectroscopy (CeMOS) at Mannheim University of Applied Sciences and published in Analytical Chemistry.

Amyloid plaques have always been thought of as homogenous structures. However, a surprising degree of variation among these plaques was discovered using a potent new technology called multimodal mass spectrometry imaging in conjunction with machine learning, which was used in the Hopf lab.

Our research completely redefines our understanding of amyloid plaques, by analyzing individual plaques at the single-molecule level, we discovered that their compositions vary quite a bit. Plaques contain different levels of Aβ and other fatty molecules called lipids. Moreover, the specific makeup seems to differ significantly between patients with full-blown AD and those who have amyloid deposits but no cognitive decline.”

Dr. Thomas Enzlein, Study First Author, VIB-KU Leuven

The development of precise diagnostic tools capable of differentiating between those at risk of cognitive decline and those who might not progress to AD is greatly enhanced by the ability to discriminate between “harmful” and “benign” plaques based on their molecular fingerprint. It also opens the door for tailored treatments that target particular plaque compositions.

A Multifaceted Approach to Combat Alzheimer’s

These results demonstrate the complexity of AD and the demand for a multimodal strategy to treat the condition.

More research is needed, but by understanding how Aβ disrupts cellular functions and the variations within amyloid plaques, we can develop better strategies to combat this devastating disease.”

Lucía Chávez Gutiérrez, Professor, VIB-KU Leuven