Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Aβ-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Aβ. Induced degeneration of the locus ceruleus increased expression of inflammatory mediators in APP-transgenic mice and resulted in elevated Aβ deposition. In vivo laser microscopy confirmed a reduced recruitment of microglia to Aβ plaque sites and impaired microglial Aβ phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Aβ clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.neuroinflammation | amyloid beta | neurodegeneration | phagocytosis A lzheimer's disease (AD) is characterized by neocortical and hippocampal atrophy due to neuronal loss, the deposition of Aβ peptides, and the formation of neurofibrillar tangles. In addition, there is a progressive degeneration of cholinergic nuclei in the basal forebrain and of noradrenergic nuclei in the brainstem, most importantly the locus ceruleus (LC). This nucleus is the major source of norepinephrine (NE) supply in the mammalian brain. The LC provides the neurotransmitter via an extensive network of neuronal projections to all major brain regions. These regions include the neocortex and hippocampus, the seat of cognitive functions, learning, and memory.Research dating back to the 1960s implicated LC degeneration in the pathogenesis of AD (1-3). Of particular relevance, several studies show that AD patients present with a prominent loss of LC cells, reaching 70% within the rostral nucleus and causing reduction of cortical and limbic NE levels (4). The drop in NE concentration tightly correlates with the progression and extent of memory dysfunction and cognitive impairment. Degeneration of LC neurons has been observed in patients exhibiting "mild cognitive impairment" (MCI) (5), an early form of AD, with 80% of MCI patients eventually succumbing to full AD (6).Degeneration of LC neurons results in progressive loss of two different types of axons, those with either conventional synaptic contacts or varicosities. Varicosities are believed to release transmitter extrasynaptically into the microenvironment, where it may act on surrounding neurons, glial cells, and blood vessels (7). Locally diffusing NE is thought to execute additional functions apart from its role as a classical neurotransmitter. Indeed, NE negatively regulates transcription of inflammatory genes in astrocytes and microglia (8), both expressi...

The hypothesis that amyloid pathology precedes and induces the tau pathology of Alzheimer's disease is experimentally supported here through the identification of GSK-3 isozymes as a major link in the signaling pathway from amyloid to tau pathology. This study compares two novel bigenic mouse models: APP-V717I x Tau-P301L mice with combined amyloid and tau pathology and GSK-3beta x Tau-P301L mice with tauopathy only. Extensive and remarkable parallels were observed between these strains including 1) aggravation of tauopathy with highly fibrillar tangles in the hippocampus and cortex; 2) prolonged survival correlated to alleviated brainstem tauopathy; 3) development of severe cognitive and behavioral defects in young adults before the onset of amyloid deposition or tauopathy; and 4) presence of pathological phospho-epitopes of tau, including the characteristic GSK-3beta motif at S396/S404. Both GSK-3 isozymes were activated in the brain of parental APP-V717I amyloid mice, even at a young age when cognitive and behavioral defects are evident but before amyloid deposition. The data indicate that amyloid induces tauopathy through activation of GSK-3 and suggest a role for the kinase in maintaining the functional integrity of adult neurons.

Generation of neurotoxic amyloid beta peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer's disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction, may actively contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzyme systems are expressed and released by microglia, astrocytes and neurons in the AD brain. Degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may facilitate the occurrence of inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate amyloid precursor protein processing by various means and therefore can establish a vicious cycle. Despite the fact that some aspects of inflammation may even be protective for bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal anti-inflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. While, the precise molecular mechanism underlying this effect is still unknown, a number of possible mechanisms including cyclooxygenase 2 or gamma-secretase inhibition and activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection.

Brains of Alzheimer’s disease patients are characterized by the presence of amyloid plaques and neurofibrillary tangles, both invariably associated with neuroinflammation. A crucial role for NLRP3–ASC inflammasome [NACHT, LRR and PYD domains-containing protein 3 (NLRP3)–Apoptosis-associated speck-like protein containing a CARD (ASC)] in amyloid-beta (Aβ)-induced microgliosis and Aβ pathology has been unequivocally identified. Aβ aggregates activate NLRP3–ASC inflammasome (Halle et al. in Nat Immunol 9:857–865, 2008) and conversely NLRP3–ASC inflammasome activation exacerbates amyloid pathology in vivo (Heneka et al. in Nature 493:674–678, 2013), including by prion-like ASC-speck cross-seeding (Venegas et al. in Nature 552:355–361, 2017). However, the link between inflammasome activation, as crucial sensor of innate immunity, and Tau remains unexplored. Here, we analyzed whether Tau aggregates acting as prion-like Tau seeds can activate NLRP3–ASC inflammasome. We demonstrate that Tau seeds activate NLRP3–ASC-dependent inflammasome in primary microglia, following microglial uptake and lysosomal sorting of Tau seeds. Next, we analyzed the role of inflammasome activation in prion-like or templated seeding of Tau pathology and found significant inhibition of exogenously seeded Tau pathology by ASC deficiency in Tau transgenic mice. We furthermore demonstrate that chronic intracerebral administration of the NLRP3 inhibitor, MCC950, inhibits exogenously seeded Tau pathology. Finally, ASC deficiency also decreased non-exogenously seeded Tau pathology in Tau transgenic mice. Overall our findings demonstrate that Tau-seeding competent, aggregated Tau activates the ASC inflammasome through the NLRP3–ASC axis, and we demonstrate an exacerbating role of the NLRP3–ASC axis on exogenously and non-exogenously seeded Tau pathology in Tau mice in vivo. The NLRP3–ASC inflammasome, which is an important sensor of innate immunity and intensively explored for its role in health and disease, hence presents as an interesting therapeutic approach to target three crucial pathogenetic processes in AD, including prion-like seeding of Tau pathology, Aβ pathology and neuroinflammation.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-01957-y) contains supplementary material, which is available to authorized users.