The blue spot: where seeds of destruction begin

Neuroscientist and geneticist David Weinshenker makes a case that the locus coeruleus (LC), a small region of the brainstem and part of the pons, is among the earliest regions to show signs of degeneration in both Alzheimer’s and Parkinson’s disease. You can check it out in Trends in Neurosciences.

The LC is the main source of the neurotransmitter norepinephrine in the brain, and gets its name (Latin for “blue spot”) from the pigment neuromelanin, which is formed as a byproduct of the synthesis of norepinephrine and its related neurotransmitter dopamine. The LC has connections all over the brain, and is thought to be involved in arousal and attention, stress responses, learning and memory, and the sleep-wake cycle.

Cells in the locus coeruleus are lost in mild cognitive impairment and Alzheimer’s. From Kelly et al Acta Neuropath. Comm. (2017) via Creative Commons

The protein tau is one of the toxic proteins tied to Alzheimer’s, and it forms intracellular tangles. Pathologists have observed that precursors to tau tangles can be found in the LC in apparently healthy people before anywhere else in the brain, sometimes during the first few decades of life, Weinshenker writes. A similar bad actor in Parkinson’s, alpha-synuclein, can also be detected in the LC before other parts of the brain that are well known for damage in Parkinson’s, such as the dopamine neurons in the substantia nigra.

“The LC is the earliest site to show tau pathology in AD and one of the earliest (but not the earliest) site to show alpha-synuclein pathology in PD,” Weinshenker tells Lab Land. “The degeneration of the cells in both these diseases is more gradual. It probably starts in the terminals/fibers and eventually the cell bodies die.”

A few researchers studying brain degeneration noticed the importance of the locus coeruleus in the 1980s, but it was influential German pathologist Heiko Braak who brought it back to the attention of the field in 2011.

There is some evidence that as the LC starts to malfunction, it contributes to very early symptoms of Alzheimer’s disease and Parkinson’s disease such as sleep disorders, depression, and anxiety. Furthermore, it or nearby regions may “seed” the rest of the brain with toxic proteins such as tau. But because the cells don’t die right away, there may be a window of opportunity for intervention – possibly aimed at either norepinephrine or at preserving cells in the locus coeruleus.

Weinshenker and his colleagues have recently published papers showing that:

*poisoning the LC accelerates degeneration and cognitive impairment caused by tau in a mouse model

*activating the LC artificially in an engineered system can stave off cognitive problems in a transgenic rat model

This second paper in Brain, with former postdoc Jacki Rorabaugh as first author, uses a transgenic rat, TgF344-AD, which “is the only model of Alzheimer’s disease that displays endogenous tau pathology in the locus coeruleus.” See here for commentary. A June 2018 report from Canada shows that high sugar combines with a locus coeruleus neurotoxin (DSP4, the same one used by Weinshenker’s lab) to produce Alzheimer’s-related pathologies in genetically wild-type mice.

In a clinical trial, Emory investigators have been studying the effects of atomoxetine, which boosts norepinephrine signaling, in mild cognitive impairment. The trial has concluded but results are not yet reported. In addition, neurologist Dan Huddleston and colleagues have been developing methods for estimating the volume of the locus coeruleus by magnetic resonance imaging (MRI). Their procedure uses MRI tuned in such a way to detect neuromelanin, and has the potential to aid in early diagnosis of Alzheimer’s disease and Parkinson’s disease.




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Quinn Eastman

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