Neuronal Degeneration in Locus Ceruleus and Cortical Correlates of Alzheimer Disease

Bondareff, William; Mountjoy, C.Q.; Roth, Michaela; Rossor, Martin N.; Ll, Iversen; Reynolds, G.P.; Hauser, Douglas L.

doi:10.1097/00002093-198701040-00005

Cited by 154 publications

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“…LC degeneration is a well known feature of AD (Forno, 1966) and correlates with its clinical and histopathological changes (Bondareff et al, 1987;Zarow et al, 2003). Loss of LC neurons occurs early in AD (German et al, 1992) and subsequently attenuates the allocation of NA to respective projection areas (Adolfsson et al, 1979;Mann et al, 1980).…”

Section: Discussionmentioning

confidence: 99%

“…LC degeneration and the subsequent loss of arising axons result in decreased noradrenaline (NA) levels in respective brain regions of AD patients (Adolfsson et al, 1979;Mann et al, 1980;Matthews et al, 2002). The reduction of LC neurons correlates with amyloid-␤ (A␤) plaques, neurofibrillary tangles, and the severity of dementia (Bondareff et al, 1987). LC neurons also show ectopic expression of cell cycle proteins predictive of cell death (Busser et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice

et al. 2006

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Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer's disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice

et al. 2006

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“…Research dating back to the 1960s implicated LC degeneration in the pathogenesis of AD (1)(2)(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).…”

mentioning

confidence: 99%

Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

Heneka

Nadrigny

Regen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

445

420

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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...

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“…This nucleus plays a major role in attention, behavioral flexibility, and cognitive processes [67][68][69]. In the normal human brain the right and left nuclei combined contain at most 50,000 noradrenergic neurons [70][71], and the number is decreased in Alzheimer's disease [72][73]. Ascending fibers from locus coeruleus constitute the dorsal noradrenergic bundle, which contains noradrenergic fibers but no adrenergic fibers and supplies the cerebral cortex with virtually its entire source of noradrenaline [74][75].…”

Section: Locus Coeruleusmentioning

confidence: 99%

“…In Alzheimer's disease there is pronounced cell death of noradrenergic neurons in locus coeruleus, especially in those parts, which extend processes to the vulnerable parts of the brain [70][71][72][382][383][384][385][386]. In contrast the caudal part of the nucleus sending projections to non-cortical regions is spared [387].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Hertz¹,

Chen²,

Gibbs³

et al. 2004

CDTCNSND

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Considerable attention has recently been paid to astrocyte functions, which are briefly summarized. A large amount of data is available about adrenoceptor expression and function in astrocytes, some of it dating back to the 1970's and some of it very recent. This material is reviewed in the present paper. The brain is innervated by noradrenergic fibers extending from locus coeruleus in the brain stem, which in turn is connected to a network of adrenergic and noradrenergic nuclei in the medulla and pons, contributing to the control of (nor)adrenergic, serotonergic, dopaminergic and cholinergic function, both in the central nervous system (CNS) and in the periphery. In the CNS astrocytes constitute a major target for noradrenergic innervation, which regulates morphological plasticity, energy metabolism, membrane transport, gap junction permeability and immunological responses in these cells. Noradrenergic effects on astrocytes are essential during consolidation of episodal, long-term memory, which is reinforced by β-adrenergic activation. Glycogenolysis and synthesis of glutamate and glutamine from glucose, both of which are metabolic processes restricted to astrocytes, occurs at several time-specific stages during the consolidation. Astrocytic abnormalities are almost certainly important in the pathogenesis of multiple sclerosis and in all probability contribute essentially to inflammation and malfunction in Alzheimer's disease and to mood disturbances in affective disorders. Noradrenergic function in astrocytes is severely disturbed by chronic exposure to cocaine, which also changes astrocyte morphology. Development of drugs modifying noradrenergic receptor activity and/or down-stream signaling is advocated for treatment of several neurological/psychiatric disorders and for neuroprotection. Astrocytic preparations are suggested for study of mechanism(s) of action of antidepressant drugs and pathophysiology of mood disorders.

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Neuronal Degeneration in Locus Ceruleus and Cortical Correlates of Alzheimer Disease

Cited by 154 publications

References 0 publications

Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice

Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice

Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

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