A new protein that may contribute to Alzheimer’s disease has been identified

Summary: GM2A protein reduces neural firing and reduces neurite integrity.

Source: Brigham and Women’s Hospital

Alzheimer’s disease (AD) currently has no cure and is predicted to affect more than 100 million people worldwide by 2050.

Ongoing research focuses on two key neurotoxic proteins: amyloid beta (Aβ) and tau. Although these proteins have been shown to be associated with AD, for some people with the disease, levels of Aβ and tau do not consistently explain or correlate with the severity of cognitive decline.

To identify other proteins that may be directly involved in fundamental aspects of AD, such as synaptic loss and neurodegeneration, investigators at Brigham and Women’s Hospital, a founding member of the Mass General Brigham Health Care System, uncovered laboratory neurons from brain extracts of about 40 people. Those who either had AD were protected from AD despite having high Aβ and tau levels, or were protected from AD despite having little or no Aβ and tau in their brains.

Researchers identified and validated ganglioside GM2 activator (GM2A) as a protein capable of reducing neuronal firing and reducing neurite integrity. These protein properties may contribute to AD causation, disease progression, or both.

“Our data help identify a new and potentially important protein that may be linked to the pathogenesis of Alzheimer’s disease,” said senior author Tracy Young-Pearce, Ph.D., from the Department of Neurology.

“Surprisingly, GM2A has previously been implicated as a causative agent in a lysosomal storage disorder like Tay-Sachs disease, another AD-like condition that destroys neurons.”

Alzheimer’s disease research news

Author: Haley Bridger
Source: Brigham and Women’s Hospital
Contact: Haley Bridger – Brigham and Women’s Hospital
Image: Image is in public domain

Original Research: Access to all,
“Elevated ganglioside GM2 activator (GM2A) in human brain tissue reduces neurite integrity and spontaneous neuronal activity.“By Tracy Young-Pearce et al. Molecular neurodegeneration

---

abstract

Elevated ganglioside GM2 activator (GM2A) in human brain tissue reduces neurite integrity and spontaneous neuronal activity.

Background

Alzheimer’s disease (AD) affects millions of people worldwide, but the development of therapies lags behind. New experimental systems that monitor neuronal function in conditions that approximate the AD brain may be useful for identifying new therapeutic strategies.

method

We characterized neurons cultured from aqueous-soluble human brain extracts from 43 individuals across a spectrum of AD pathology. Multi-electrode arrays (MEAs) and live-cell imaging were used to assess neuronal firing and neurite integrity (NI), respectively, following treatment of rat cortical neurons (MEA) and human iPSC-derived neurons (iN) with human brain extract. .

result

We observed correlations between spontaneous activity and Aβ42:40 levels, between neurite integrity and oligomeric Aβ, and between neurite integrity and tau levels present in brain extracts. However, these associations with Aβ and tau do not fully account for the observed effects. Proteomic profiling of brain extracts revealed additional candidates associated with neuronal structure and activity. Neurotoxicity in the MEA and NI assays was associated with proteins involved in lysosomal storage disorders, while neuroprotection was associated with proteins in actin cytoskeleton dynamics controlling the WAVE regulatory complex. Elevated ganglioside GM2 activator (GM2A) is associated with reduced both NI and MEA activity, and cell-derived GM2A alone is sufficient to reduce neurite integrity and decrease neuronal firing.

Conclusion

The techniques and data here introduce a system for modeling neuronal vulnerability in response to human brain factors and provide insight into proteins that potentially contribute to AD pathogenesis.