Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: Possible implications for diagnosis and treatment

Haglund, Mattias; Sjöbeck, Martin; Englund, Elisabet

doi:10.1111/j.1440-1789.2006.00725.x

Cited by 75 publications

(56 citation statements)

References 31 publications

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“…This fading is paralleled by the underactivity of the C1(Ad) nuclei in such a way that aging is always accompanied by the progressive predominance of the A5(NA)-neural sympathetic activity. These findings are also consistent with facts showing that most psychiatric disturbances -psychosis [67,105,116,117], attention-deficit hyperactive disorder [65], posttraumatic-stress-disorder [118,119], and Alzheimer disease [120] -are underlain by the underactivity of the A6(NA) plus the predominance of the A5(NA) neurons that are responsible for the peripheral neural sympathetic system [121][122][123][124][125][126][127]. This latter explains the raised NA/Ad ratio always registered in these patients.…”

Section: Physiological Evidencesupporting

confidence: 79%

Central Nervous System Circuitries Underlying Two Types of Peripheral Autonomic Nervous System Disorders~!2008-04-24~!2008-09-26~!2008-12-05~!

Lechín¹,

Dijs²

2008

TONEURJ

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Abstract:The assessment of circulating neurotransmitters: noradrenaline, adrenaline, dopamine, platelet serotonin, plasma serotonin and plasma tryptophan before and after many types of stressor agents and neuropharmacological drugs carried out over the last thirty years allowed us to accumulate information dealing with the central nervous system (CNS) versus the peripheral autonomic nervous system (ANS) interactions in healthy as well as diseased mammals. Furthermore, the accurate knowledge about the CNS circuitry disorders which underlie both the CNS and peripheral clinical syndromes, has allowed us to prescribe successful neuropharmacological therapeutical strategies for many types of illnesses. In addition, the demonstration that the clinical improvement was always paralleled by the normalization of the neurochemical, hormonal, immunological and clinical profiles affords strong support to our point of view. According to all the above, the authors postulate the existence of two types of diseases: type A and Type N, which are underlain by two opposite CNS + ANS disorders. Type A diseases should be associated with the "uncoping stress" syndrome and are underlain by hyperactivity of the adrenocortical glands plus the CNS disorder characterized by the predominance of the C1(adrenergic) + DR(serotonergic) axis over the A5(noradrenergic) + MR(serotonergic) binomial, whereas the type N diseases depends on the opposite profile: "endogenous depression" syndrome. Finally, we quoted exhaustive evidence showing that the well known fading of both the A6(noradrenergic) + C1(adrenergic) CNS nuclei activity occurring during aging is responsible for the ANS + CNS disorder which is similar to that underlying psychosis, Alzheimer, post-traumatic stress disorder and deficit-attention hyperactive disorder.

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Section: Physiological Evidencesupporting

confidence: 79%

Central Nervous System Circuitries Underlying Two Types of Peripheral Autonomic Nervous System Disorders~!2008-04-24~!2008-09-26~!2008-12-05~!

Lechín¹,

Dijs²

2008

TONEURJ

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“…However, in a recent study, although LC was a consistent feature that distinguished AD from vascular dementia, no correlation was found between the degree of LC degeneration and duration of dementia or severity of AD pathology. 26 Parkinson disease. Degeneration of the LC is an early event that precedes degeneration of dopaminergic neurons of the substantia nigra pars compacta in PD.…”

Section: Functions Of the Lc-ne System In Thementioning

confidence: 99%

The locus ceruleus norepinephrine system

Benarroch¹

2009

Neurology

294

227

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The locus ceruleus (LC) contains norepinephrine (NE)-synthesizing neurons that send diffuse projections throughout the CNS. The LC-NE system has a major role in arousal, attention, and stress response. In the brain, NE may also contribute to long-term synaptic plasticity, pain modulation, motor control, energy homeostasis, and control of local blood blow. The LC is severely affected in neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Dysregulation of LC-NE system has been implicated in sleep and arousal disorders, attention deficit hyperactivity disorder, and posttraumatic stress disorder and constitutes a target for pharmacologic treatment of these conditions. The neurobiology of the LC-noradrenergic system has been the subject of several excellent reviews. 1-9 FUNCTIONAL ANATOMY OF THE LOCUS CER-ULEUSThe LC is a cluster of NE-containing neurons located in the upper dorsolateral pontine tegmentum (figure 1). These neurons have extensively branched axons that project throughout the neuraxis and provide the sole source of NE to the neocortex, hippocampus, cerebellum, and most of the thalamus. 1,2 Despite its widespread distribution, noradrenergic innervation shows regional specificity. For example, brain areas involved in spatial attention (such as the prefrontal and parietal cortices) receive particularly dense LC-NE inputs. In general, individual LC neurons send axon collaterals to multiple targets that process the same sensory information. Norepinephrine is released both at typical synapses and at nonsynaptic release sites; extrasynaptic NE mediates paracrine effects on neurons, glial cells, and microvessels. [1][2][3][4]8 NEUROCHEMISTRY AND PHARMACOLOGY OF THE CENTRAL NORADRENERGIC SYSTEM Norepinephrine is synthesized from tyrosine by tyrosine hydroxylase with formation of L-dihydroxyphenylalanine (L-DOPA), which is converted to dopamine by L-amino acid decarboxylase. Dopamine is transported into synaptic vesicles by the vesicular monoamine transporter and converted within the synaptic vesicles to NE by action of the dopamine ␤-hydroxylase (DBH). The main mechanism of NE inactivation is its presynaptic reuptake via a selective NE transporter (NET), followed by metabolism by monoamine oxidase A and catechol-O-methyltransferase, with formation of 3-methoxy-4-hydroxyphenylglycol.Norepinephrine acts via three G-protein receptor families, ␣ 1 , ␣ 2 , and ␤, each consisting of several subtypes. 4,10 In the nervous system, ␣ 1 and ␤ receptors exist primarily at postsynaptic sites, where they generally exert an excitatory action; ␣ 2 receptors exist both pre-and postsynaptically, where they commonly have inhibitory effects. 8 The distribution and second messenger coupling of these receptor subtypes vary within and across brain regions (table 1). In general, the synaptic availability of NE is regulated by 2 mechanisms, active reuptake via the NET and inhibition of release via presynaptic ␣ 2 autoreceptors. The NET is inhibited by cocaine, amphetamine, venlafaxine, duloxetine, and r...

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“…Profound dysfunction of the NA system consistently occurs at the early stage of AD (21), raising the possibility of involvement of the α 2A AR in AD pathogenesis. Here we report for the first time to our knowledge that α 2A AR signaling regulates SorLA-dependent APP sorting and promotes amyloidogenic processing of APP by beta-site amyloid precursor Significance Endocytic sorting of amyloid precursor protein (APP) governed by the vacuolar protein sorting (Vps10) family of receptors plays a decisive role in controlling the outcome of APP proteolytic processing and the generation of amyloid β (Aβ) peptides, the key pathogenic factor of Alzheimer's disease (AD).…”

mentioning

confidence: 99%

α _2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction

Chen

Peng

Che

et al. 2014

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

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Accumulation of amyloid β (Aβ) peptides in the brain is the key pathogenic factor driving Alzheimer's disease (AD). Endocytic sorting of amyloid precursor protein (APP) mediated by the vacuolar protein sorting (Vps10) family of receptors plays a decisive role in controlling the outcome of APP proteolytic processing and Aβ generation. Here we report for the first time to our knowledge that this process is regulated by a G protein-coupled receptor, the α 2A adrenergic receptor (α 2A AR). Genetic deficiency of the α 2A AR significantly reduces, whereas stimulation of this receptor enhances, Aβ generation and AD-related pathology. Activation of α 2A AR signaling disrupts APP interaction with a Vps10 family receptor, sorting-related receptor with A repeat (SorLA), in cells and in the mouse brain. As a consequence, activation of α 2A AR reduces Golgi localization of APP and concurrently promotes APP distribution in endosomes and cleavage by β secretase. The α 2A AR is a key component of the brain noradrenergic system. Profound noradrenergic dysfunction occurs consistently in patients at the early stages of AD. α 2A AR-promoted Aβ generation provides a novel mechanism underlying the connection between noradrenergic dysfunction and AD. Our study also suggests α 2A AR as a previously unappreciated therapeutic target for AD. Significantly, pharmacological blockade of the α 2A AR by a clinically used antagonist reduces AD-related pathology and ameliorates cognitive deficits in an AD transgenic model, suggesting that repurposing clinical α 2 AR antagonists would be an effective therapeutic strategy for AD.adrenergic receptor | amyloid | processing | SorLA | sorting E xcess amyloid β (Aβ) peptides in the brain are a neuropathological hallmark of Alzheimer's disease (AD) and are generally accepted as the key pathogenic factor of the disease (1). Aβ is generated by two sequential cleavages of amyloid precursor protein (APP) by β and γ secretase, whereas cleavage by α secretase within the Aβ domain precludes Aβ generation (2, 3). APP and the secretases undergo endocytic sorting into various organelles, such as the trans-Golgi network, the plasma membrane, and endosomes (2-6). The initial step of APP processing by α versus β secretase preferentially occurs in distinct compartments of the cell. Although α secretase-mediated cleavage of APP occurs on the plasma membrane, β secretase primarily interacts with and cleaves APP in endosomes (2-6). Therefore, endocytic sorting of APP into different membranous compartments, causing it to coreside or avoid a particular secretase, plays a decisive role in APP proteolytic processing. Consistent with this notion, abnormalities of the endocytic pathway have been found to precede Aβ deposition in late-onset AD (7).Retrograde sorting of APP from endosomes to trans-Golgi network mediated by the vacuolar protein sorting-10 (Vps10) family proteins and the retromer complex represents a critical mechanism to prevent amyloidogenic processing of APP (8-10) and has recently emerged as a potential targe...

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Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: Possible implications for diagnosis and treatment

Cited by 75 publications

References 31 publications

Central Nervous System Circuitries Underlying Two Types of Peripheral Autonomic Nervous System Disorders~!2008-04-24~!2008-09-26~!2008-12-05~!

Central Nervous System Circuitries Underlying Two Types of Peripheral Autonomic Nervous System Disorders~!2008-04-24~!2008-09-26~!2008-12-05~!

The locus ceruleus norepinephrine system

α _2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction

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Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: Possible implications for diagnosis and treatment

Cited by 75 publications

References 31 publications

Central Nervous System Circuitries Underlying Two Types of Peripheral Autonomic Nervous System Disorders~!2008-04-24~!2008-09-26~!2008-12-05~!

Central Nervous System Circuitries Underlying Two Types of Peripheral Autonomic Nervous System Disorders~!2008-04-24~!2008-09-26~!2008-12-05~!

The locus ceruleus norepinephrine system

α 2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction

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α _2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction