David Weinshenker’s lab recently published a study examining the effects of pathological Tau protein in mice, when introduced into the brain in a limited way. The results were published in Molecular Psychiatry.
Part of the brainstem, the locus coeruleus is one of the first regions of the brain impacted by Alzheimer’s pathology, as defined by the work of renowned German neuropathologists Heiko and Eva Braak. Hyperphosphorylated Tau has been observed in the locus coeruleus of healthy middle-aged people, before other forms of Alzheimer’s pathology such as tangles and plaques, and before they appear in other parts of the brain. The locus coeruleus is also the main source of the neurotransmitter norepinephrine.
Graduate student Anu Korukonda and colleagues sought to recreate the very first observable stage of Alzheimer’s pathology in mice, by expressing a mutant form of Tau in the locus coeruleus with a viral vector. The Tau variant they used, P364S, is actually associated with frontotemporal dementia (not Alzheimer’s). It was chosen because it produces pathology similar to what is observed in Alzheimer’s brains and is less likely to form Tau aggregates that spread from cell to cell, thus restricting it to locus coeruleus neurons. Thus, this experiment was designed to simulate only the initial stages of Alzheimer’s brain pathology and not subsequent stages.
In mice examined three months after viral vector injection, expressing mutant Tau leads to anxiety- and compulsive-like behaviors, along with subtle disruptions of sleep (a reduction in a kind of brain wave called spindles, without big changes in sleep architecture). Looking more closely, the authors saw hyperactivity of the locus coeruleus and reactive astrocytes, without substantial cell death. However, behavioral changes did not persist in viral vector-injected mice after six or nine months.
The authors say the findings support the idea that Tau-induced locus coeruleus hyperactivity contributes to early neuropsychiatric symptoms previewing progression to Alzheimer’s, such as anxiety/agitation and disrupted sleep.
Collaborators included Beckstead lab (OMRF, electrophysiology), Rangaraju lab (Emory Yale, proteomics), Varga lab (Mt. Sinai, sleep), and Martinowich lab (Hopkins, transcriptomics).
This study in mice is part of a larger body of evidence suggesting that stabilizing the locus coeruleus before Alzheimer’s progression proceeds too far could be beneficial. Interventions such as norepinephrine-boosting atomoxetine have been tested in clinical studies. And MRI imaging of the locus coeruleus has been studied as a predictor of Alzheimer’s disease progression.