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Kang SS, Meng L, Zhang X, Wu Z, Mancieri A, Xie B, Liu X, Weinshenker D, Peng J, Zhang Z, Ye K. Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation. Nat Struct Mol Biol. 2022 Apr;29(4):292-305. Epub 2022 Mar 24 PubMed.
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Cambridge University
This is a very important paper, placing norepinephrine and the locus coeruleus center stage in Alzheimer’s disease (and perhaps in other tauopathies where the LC is also vulnerable). The LC is small—just 50,000 neurons in adult humans—but these cells each project widely throughout the brain.
Previous work has shown the very early involvement of the locus coeruleus in the tau pathology of AD; the secondary effects of NE on neuroinflammatory cascades in AD; and the effect of LC/NE loss on cognition, as the basis of noradrenergic clinical trials like ADMET and NORAD.
But this study is different. It addresses the questions of (i) why is the LC an origin of tauopathy and (ii) how might this promote the propagation of pathology? The answers are important for their therapeutic potential.
Kang et al. demonstrate several mechanisms by which the NE metabolite DOPEGAL may interact and facilitate AD pathogenesis. It selectively stimulates formation of fibrils via a single residue, Lys353, and these fibrils are proteinase resistant; it increases intraneuronal tau pathology, with enhanced seeding efficacy; it does so under the partial control of MAO-A; and it triggers synaptotoxic and cytotoxic pathways.
Of particular value is the team’s approach to bridge all the way from structural biology, via HEK293 cell models, primary neurons, and transgenic (P301S) mice to postmortem human brain tissue. This is a model approach. The authors also demonstrate proof of concept that inhibition of MAO-A and modification of Lys353 reduces the formation and spread of tau pathology. An important step, which guides therapeutic options. And their multilevel approach mitigates concerns about the non-physiological conditions of some of the biochemical and cellular studies.
Although the MAO-A inhibitor used here differs from those already in clinical practice (e.g., for antidepressant effects), this study highlights a potential route to treatment that might be both symptomatic and disease-modifying. Clearly experimental medicine studies would be needed to evaluate this in people with—or at risk of—AD. Such studies would need to give special consideration to the stage of the disease at which such DOPEGAL-based treatments might be expected to work.
While the LC-NE story is important to understand and treat Alzheimer’s, Kang et al. have written an exciting new chapter.
View all comments by James RoweBoston University Chobanian & Avedisian School of Medicine
This is an important finding that supports an interaction between adduct formation and protein aggregation in AD. DOPEGAL is metabolized by aldehyde reductase and aldehyde dehydrogenase. Future studies should be designed to investigate the relationship between enzymatic polymorphisms and AD risk particularly with respect to age at onset, which would be expected a priori to be younger in those individuals who do not effectively metabolize DOPEGAL.
References:
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View all comments by Marcia RatnerKatholieke Universiteit Leuven, Department of Imaging and Pathology, Laboratory of Neuropathology
Kang et al. found that the primary residue Lys 353 of the τ protein reacts with the norepinephrine metabolite DOPEGAL. This interaction stimulates the accumulation of abnormal phosphorylated τ (p-τ), as well as its aggregation and propagation. This process was inhibited by replacing the lysine residue by arginine (Lys353Arg-τ). The interaction of τ with DOPEGAL was studied in HEK293 and SH-SY5Y/HA-τ cells. Aggregation and propagation effects were studied in MAPT transgenic mice using an Lys353-DOPEGAL antibody. Upregulation of the locus coeruleus MAO activity using AAV-MAO-A led to an increased production of DOPEGAL and p-τ. Treatment with an MAO-A inhibitor reduced DOPEGAL production and improved synaptic integrity. After inducing seeding by injecting fibrillar τ and Lys353Arg-τ into the brains of MAPT transgenic mice, the authors showed that only the “regular” τ carrying the Lys353 induced seeding and propagation but not Lys353Arg-τ.
This is a very elegant study demonstrating for the first time why the locus coeruleus is the brain region affected earliest by p-τ pathology (Braak and Del Tredici , 2011). In principle, the interaction with the norepinephrine metabolite DOPEGAL seems to be essential for the abnormal phosphorylation, seeding, and propagation; at least it is a prerequisite. Whether other factors will also contribute to make real AD pathology out of p-τ accumulation, or whether this is the key event that will in any case cause AD, still needs to be clarified.
On the one hand, the stage-like propagation process starting in the locus coeruleus and ending in the primary visual cortex argues in favor of AD being initiated with this first DOPEGAL-driven p-τ accumulation. On the other hand, locus coeruleus p-τ pathology was observed in nearly all cases over the age of 40 years (Braak et al., 2011), whereas higher Braak NFT stages and amyloid pathology were restricted to less than 40 percent even in the age group 90-100 years (Braak et al., 2011) indicating that not everyone exhibiting p-τ in the locus coeruleus will develop AD during life. Moreover, p-τ accumulation occurs physiologically in the status of hibernation and disappears after arousal (Arendt et al., 2003). These two points argue in favor of the hypothesis that p-τ accumulation per se is not sufficient to proceed to AD in any case, but it is very likely a prerequisite enabling the AD process to be started.
Probably Aβ may play an accelerating role here, as it aggravates p-τ pathology and its propagation (Gomes et al., 2019; Götz et al., 2001; Lewis et al., 2001), probably via a PrPC-related mechanism (Corbett et al., 2020; Gomes et al., 2019). This is integrated in the concept of primary age-related tauopathy (PART) developing into AD and being a prerequisite of this disease (Jellinger et al., 2015; Spires-Jones et al., 2017).
The potential role of norepinephrine metabolism in this process will be an important factor in understanding p-τ and its potential physiological/pathological roles. In hibernating animals, the production of p-τ is physiological and reversible (Arendt et al., 2003). If there is a border between reversible p-τ and AD p-τ, it is currently being discussed that this border may be influenced by the different phosphorylation sites of τ becoming phosphorylated at certain steps of the τ pathology development (Aragão Gomes et al., 2021).
Whether stress and sleep have an impact on p-τ formation, and whether the generation of p-τ has a sleep/stress-related role, needs to be further analyzed and will teach us about lifestyle influence on τ pathology. The role of MAO-A as shown by Kang et al., and the involvement of p-τ in the hibernation process of the brain, could argue in favor of this hypothesis.
The distribution pattern of AD-related granulovacuolar degeneration in regions related to the chronic stress response and to sleep wakefulness, all receiving input from the locus coeruleus (Thal et al., 2011), may support the link to AD. The reason for this is that granulovacuolar degeneration has been reported to be induced by p-τ (Wiersma et al. 2019) and appears to be critically involved in AD-related neuron loss via necroptosis (Koper et al., 2020).
References:
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