Summary: The GM2A protein reduces neural firing and induces a loss of neurite integrity.

Source: Brigham and Womens Hospital

Alzheimers disease (AD) currently has no cure and is predicted to affect over 100 million people worldwide by 2050.

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

To identify other proteins that may be directly involved with fundamental aspects of AD, like synaptic loss and neurodegeneration, investigators at Brigham and Womens Hospital, a founding member of the Mass General Brigham healthcare system, exposed laboratory neurons to human brain extracts from about 40 people who either had AD, were protected from AD despite having high A and tau levels, or were protected from AD with little or no A and tau in their brains.

The researchers identified and validated ganglioside GM2 activator (GM2A) as a protein able to reduce neuronal firing and induce a loss of neurite integrity. These protein characteristics may contribute to the cause of AD, progression of the disease, or both.

Our data helps identify a new and potentially important protein that may be associated with the pathogenesis of Alzheimers disease, said senior author Tracy Young-Pearse, PhD, from the Department of Neurology.

Interestingly, GM2A has been previously implicated as a causative agent in a lysosomal storage disorder very similar to Tay-Sachs disease, another condition like AD that destroys neurons.

Author: Haley BridgerSource: Brigham and Womens HospitalContact: Haley Bridger Brigham and Womens HospitalImage: The image is in the public domain

Original Research: Open access,Elevated ganglioside GM2 activator (GM2A) in human brain tissue reduces neurite integrity and spontaneous neuronal activity by Tracy Young-Pearse et al. Molecular Neurodegeneration

Abstract

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

Alzheimers Disease (AD) affects millions globally, but therapy development is lagging. New experimental systems that monitor neuronal functions in conditions approximating the AD brain may be beneficial for identifying new therapeutic strategies.

We expose cultured neurons to aqueous-soluble human brain extract 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 treatments of rat cortical neurons (MEA) and human iPSC-derived neurons (iN) with human brain extracts.

We observe associations between spontaneous activity and A42:40 levels, between neurite integrity and oligomeric A, and between neurite integrity and tau levels present in the brain extracts. However, these associations with A and tau do not fully account for the effects observed. Proteomic profiling of the brain extracts revealed additional candidates correlated with neuronal structure and activity. Neurotoxicity in MEA and NI assays was associated with proteins implicated in lysosomal storage disorders, while neuroprotection was associated with proteins of the WAVE regulatory complex controlling actin cytoskeleton dynamics. Elevated ganglioside GM2 activator (GM2A) associates with reductions in both NI and MEA activity, and cell-derived GM2A alone is sufficient to induce a loss of neurite integrity and a reduction in neuronal firing.

The techniques and data herein introduce a system for modeling neuronal vulnerability in response to factors in the human brain and provide insights into proteins potentially contributing to AD pathogenesis.

Continue reading here:
A New Protein That May Contribute to Alzheimers Disease Identified - Neuroscience News