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New Bio-markers in Alzheimer’s & Stress Induced Changes in the Brains of Alzheimer’s Patients

Posted in Alzheimer's Disease, Etiology, Uncategorized, tagged Alzheimer, Alzheimers Disease, BUSM, Journal of Neuroscience, RNA, RNA-binding protein, Stress, Tau protein, TIA1 on June 26, 2012| 5 Comments »

Curated by: Dr. Venkat S. Karra, Ph.D

Nuerodegenertive disease – Alzheimer’s – is presumed to be caused by the accumulation of β-amyloid.

The diagnosis of Alzheimer’s disease focuses on

β-amyloid protein and

tau protein

Though much attention is on radiolabeled markers, imaging βamyloid is problematic because many cognitively normal elderly have large amounts of β-amyloid in their brain, and appear as “positives” in the imaging tests.

At the same time therapeutic approaches for Alzheimer’s disease have not been focused much on the process of producing a neurofibrillary tangle composed on tau protein.

Various brain sections showing tau protein (Photo credit: WBUR)

Now the BUSM researchers identified a new group of proteins, termed RNA-binding proteins, which accumulate in the brains of patients with Alzheimer’s disease, and are present at much lower levels in subjects who are cognitively intact.

The researchers believe this work opens up novel approaches to diagnose and stage the likelihood of progression by quantifying the levels of these RNA-binding protein biomarkers that accumulate in the brains of Alzheimer patients.

The group found two different proteins, both of which show striking patterns of accumulation. “Proteins such as TIA-1 and TTP, accumulate in neurons that accumulate tau protein, and co-localize with neurofibrillary tangles. These proteins also bind to tau, and so might participate in the disease process,” explained senior author Benjamin Wolozin, MD, PhD, a professor in the departments of pharmacology and neurology at BUSM.

“A different RNA binding protein, G3BP, accumulates primarily in neurons that do not accumulate pathological tau protein.

This observation is striking because it shows that neurons lacking tau aggregates (and neurofibrillary tangles) are also affected by the disease process,” he added.

Wolozin’s group also pursued the observation that some of the RNA binding proteins bind to tau protein, and tested whether one of these proteins, TIA-1, might contribute to the disease process.

‘Stress’ induced aggregation of RNA-binding proteins

Previously, scientists like Tara Vanderweyde et. al., have demonstrated that TIA-1 spontaneously aggregates in response to stress as a normal part of the stress response. They examined the relationship between Stress Granules (SGs) and neuropathology in brain tissue from P301L Tau transgenic mice, as well as in cases of Alzheimer’s disease and FTDP-17.

Stress Granules (SGs) are ‘Stress’ induced aggregation of RNA-binding proteins.

The pattern of SG pathology differed dramatically based on the RNA-binding protein examined. SGs positive for T-cell intracellular antigen-1 (TIA-1) or tristetraprolin (TTP) initially did not co-localize with tau pathology, but then merge with tau inclusions as disease severity increases. In contrast, G3BP (ras GAP-binding protein) identifies a novel type of molecular pathology that shows increasing accumulation in neurons with increasing disease severity, but often is not associated with classic markers of tau pathology. TIA-1 and TTP both bind phospho-tau, and TIA-1 overexpression induces formation of inclusions containing phospho-tau. These data suggest that SG formation might stimulate tau pathophysiology.

Thus, study of RNA-binding proteins and SG biology highlights novel pathways interacting with the pathophysiology of AD.

With this understanding, Wolozin and his colleagues hypothesize that since TIA-1 binds tau, it might stimulate tau aggregation during the stress response. They introduced TIA-1 into neurons with tau protein, and subjected the neurons to stress. Consistent with their hypothesis, tau spontaneously aggregated in the presence of TIA-1, but not in the absence. Thus, the group has potentially identified an entirely novel mechanism to induce tau aggregates de novo.

In future work, the group hopes to use this novel finding to understand how neurofibrillary tangles for in Alzheimer’s disease and to screen for novel compounds that might inhibit the progression of Alzheimer’s disease.

They believe that it may open up novel approaches to diagnose and stage the progression likelihood of the disease in Alzheimer patients.