The Norepinephrine Metabolite DOPEGAL Confers Locus Coeruleus Tau Vulnerability and Propagation via Asparagine Endopeptidase

Abstract

Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer's disease (AD)-like neuropathology in the human brain; however, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear.Here we show that 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), which is produced exclusively in noradrenergic neurons by monoamine oxidase A (MAO-A) metabolism of norepinephrine (NE), activates asparagine endopeptidase (AEP) that cleaves Tau at residue N368 into aggregation-and propagation-prone forms, thereby leading to LC degeneration and the spread of Tau pathology. DOPEGAL triggers AEP-cleaved Tau aggregation in vitro and in intact cells, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal a novel molecular mechanism underlying the selective vulnerability of LC neurons in AD.Keywords neurodegenerative diseases; norepinephrine; neurofibrillary tangle; locus coeruleus; Tau 4 neurochemical characteristics (7, 16), the underlying molecular mechanisms have yet to be identified.Asparagine endopeptidase (AEP; gene name LGMN) is a lysosomal endopeptidase that specifically cleaves its substrates after asparagine under conditions of acidosis (17). Recently, we reported that AEP acts as a delta-secretase that cleaves both amyloid precursor protein (APP) andTau in an age-dependent manner in mouse and human AD brains (18, 19). AEP cuts APP at the N373 and N585 residues in the ectodomain and facilitates Aβ production by decreasing the steric hindrance for beta-secretase (BACE1). Depletion of AEP significantly reduces Aβ production and senile plaque formation in 5XFAD transgenic mice, leading to the restoration of synaptic activity and cognitive functions (19). In addition, AEP cleaves Tau at N255 and N368 and abolishes its microtubule assembly activity, resulting in hyperphosphorylation, aggregation, and NFT formation (18). Of note, the AEP-generated Tau 1-368 fragment is highly neurotoxic.Genetic deletion or pharmacological inhibition of AEP in transgenic mice that overexpress mutant human APP or aggregation-prone mutant human Tau prevents APP N585 and Tau N368 cleavage, ameliorates Aβ and Tau pathology, and reverses synaptic plasticity and cognitive deficits (18, 20). Thus, AEP plays a critical role in regulating Aβ and Tau pathogenesis. Most recently, we reported that AEP is activated by 3,4-dihydroxyphenylacetaldehyde (DOPAL), a highly toxic and oxidative dopamine (DA) metabolite, in the substantia nigra (21). Active AEP subsequently cleaves α-synuclein at N103 and promotes its aggregation and dopameringeric neuronal loss, leading to motor dysfunction in animal models of Parkinson's disease (PD) (22). 5Analogous to toxic DA metabolites killing substantia nigra pars compacta neurons in PD, the noradrenergic phenotype of LC neurons itself may contribute to the vulnerability of these cells in AD. NE is ...

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

“…2 While degeneration of the LC has long been known as a ubiquitous feature of Alzheimer's disease, [3][4][5][6][7] studies provide several lines of compelling evidence that impaired LC function in Alzheimer's disease contributes to not only the clinical symptoms, but also triggers underlying pathophysiological mechanisms involved in progressive neurodegeneration. 2,[8][9][10][11][12][13][14][15][16][17][18][19][20] Both imaging and postmortem studies indicate that volumetric reduction, neuronal loss, and neuropathology in LC predict the rate of cognitive decline, attentional and executive function deficits, and Tau burden in humans, suggesting an important role in cognitive resilience and abnormal protein aggregation. 16,[21][22][23][24][25] Hyperphosphorylated Tau, a "pretangle" form of the protein prone to aggregation, appears in the LC before any other area of the brain, and is now considered the earliest detectable Alzheimer's disease-like neuropathology, evident even in young and middle-aged adults.…”

“…14,[26][27][28][29][30][31][32] The connectivity of the LC provides a neuroanatomical substrate that may mediate the spread of pathological Tau seeds to the forebrain. 20,33 The appearance of Tau pathology in the LC is also associated with depression and sleep disturbances, important risk factors for Alzheimer's disease, 7,34 and cognitive impairment becomes evident as LC neurons start to degenerate. 19 Causal relationships between the LC and disease-modifying processes are implicated using genetic and neurotoxin-induced lesions of the LC, which exacerbate neuropathology and cognitive deficits in both amyloid-and Tau-based transgenic mouse models of Alzheimer's disease, at least in part mediated by the critical role of LC in regulation of neuroinflammation.…”

A Phase II Study Repurposing Atomoxetine for Neuroprotection in Mild Cognitive Impairment

“…2 While degeneration of the LC has long been known as a ubiquitous feature of Alzheimer's disease, [3][4][5][6][7] studies provide several lines of compelling evidence that impaired LC function in Alzheimer's disease contributes to not only the clinical symptoms, but also triggers underlying pathophysiological mechanisms involved in progressive neurodegeneration. 2,[8][9][10][11][12][13][14][15][16][17][18][19][20] Both imaging and postmortem studies indicate that volumetric reduction, neuronal loss, and neuropathology in LC predict the rate of cognitive decline, attentional and executive function deficits, and Tau burden in humans, suggesting an important role in cognitive resilience and abnormal protein aggregation. 16,[21][22][23][24][25] Hyperphosphorylated Tau, a "pretangle" form of the protein prone to aggregation, appears in the LC before any other area of the brain, and is now considered the earliest detectable Alzheimer's disease-like neuropathology, evident even in young and middle-aged adults.…”