Review
The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain

https://doi.org/10.1016/j.tics.2016.01.001Get rights and content

Trends

In late life, lower LC neural density is associated with cognitive decline.

Because of the long unmyelinated axons of its neurons, high exposure to blood flow, and location adjacent to the 4th ventricle, the LC is especially vulnerable to toxins.

The tau pathology precursor of Alzheimer's disease emerges in the LC by early adulthood in most people. However, the pathology typically spreads slowly, and only some end up with clinically evident Alzheimer's disease.

Norepinephrine helps to protect neurons from factors that accelerate Alzheimer's disease, such as inflammation and excitotoxicity.

Education and engaging careers produce late-life ‘cognitive reserve’ or effective brain performance despite encroaching pathology. Activation of the LC–NE system by novelty and mental challenge throughout life may contribute to cognitive reserve.

Research on cognitive aging has focused on how decline in various cortical and hippocampal regions influence cognition. However, brainstem regions play essential modulatory roles, and new evidence suggests that, among these, the integrity of the locus coeruleus (LC)–norepinephrine (NE) system plays a key role in determining late-life cognitive abilities. The LC is especially vulnerable to toxins and infection and is often the first place Alzheimer's-related pathology appears, with most people showing at least some tau pathology by their mid-20s. On the other hand, NE released from the LC during arousing, mentally challenging, or novel situations helps to protect neurons from damage, which may help to explain how education and engaging careers prevent cognitive decline in later years.

Section snippets

Relevance of the LC to Cognitive Aging

Neuromodulators transform the firing patterns of neurons, reconfiguring neuronal circuits in ways that can dramatically change their output 1, 2. In this review we focus on how age-related changes in the function of NE, one of the main neuromodulators, can help to explain cognitive change in aging. NE is best known for its roles in behavioral arousal and in the control of heart rate and blood pressure, but it also regulates attention, memory, and cognition [3]. Most NE in the brain comes from

LC Neuropathology in Aging

Most studies examining how LC neuron counts change with age suggest an age-related decline in LC neuron number by ∼20–40% (e.g., 11, 12, 13, 14, 15), with selective cell loss in the rostral LC compartment 16, 17. However, it should be noted that some of these studies made lifespan comparisons on the basis of brain samples in the N = 5 to 13 range 11, 12, 16 and did not exclude cases with pathology elsewhere in the brain. More recent studies either excluding cases with neurofibrillary tangles

Does Activating the LC–NE System Throughout Life Create Cognitive Reserve?

One fascinating cultural phenomena is the Flynn effect, in which successive generations have been getting smarter, at least as assessed by IQ tests [68]. There is no definitive answer as to why this has been occurring, but some researchers believe that environments have gradually become more stimulating, promoting learning. One possibility is that stimulating environments enhance cognition in part via their activation of the LC–NE pathway (e.g., [69]).

Certainly, evidence from animals indicates

Can Increasing NE Levels Help Cognition in Older Adults?

Given the associations between lower brain levels of NE and impaired cognition, as well as the impaired cellular protection discussed in previous sections, one plausible intervention could be to increase NE levels in the brains of older adults. In rat brain, long-term cardiovascular training increases NE levels [79], and NE synthesis increases during exercise [80]. Several days or weeks of exercise enhances learning and memory for the next few days, and this enhancement is blocked by

Long-Term Effects of β-Blockers

Given the evidence already discussed that NE release can protect against amyloid toxicity, and that many of the protective effects of NE are mediated by β-adrenergic receptor pathways, it seems that long-term use of β-adrenergic antagonists could accelerate Alzheimer's disease. This has major public health relevance because many older adults are prescribed β-blockers to help in managing cardiovascular disease [89]. However, epidemiological studies find contradictory relationships between taking

Concluding Remarks

In the current review we have outlined evidence suggesting that age-related change in the LC structure and NE function plays more of role in cognitive aging than has been previously appreciated. LC structural integrity in late life is associated with cognitive function 6, 26, as are NE levels in the brain 23, 45. Furthermore, many of the cognitive functions that have been identified as especially vulnerable in aging are strongly influenced by NE.

Understanding the role of the LC in cognitive

Glossary

Adrenergic antagonists
chemicals that block the action of catecholamines at adrenergic receptors.
β-Amyloid
a protein with 38–43 amino acids derived from amyloid precursor protein. In Alzheimer's disease it forms small aggregates called oligomers and eventually larger aggregates known as plaques. The oligomer form is believed to be the most damaging.
Caspases
enzymes that are crucial in apoptosis or programmed cell death.
Catecholamines
monoamine neurotransmitters derived from the amino acid tyrosine.

References (132)

  • D. Clewett

    Neuromelanin marks the spot: Identifying a locus coeruleus biomarker of cognitive reserve in healthy aging

    Neurobiol. Aging

    (2016)
  • N.I. Keren

    Histologic validation of locus coeruleus MRI contrast in post-mortem tissue

    Neuroimage

    (2015)
  • S. Kalinin

    The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease

    Neurobiol. Aging

    (2012)
  • D. Jardanhazi-Kurutz

    Distinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in APP/PS1 transgenic mice

    Neuroscience

    (2011)
  • S. Li

    Environmental novelty activates β2-adrenergic signaling to prevent the impairment of hippocampal LTP by Aβ oligomers

    Neuron

    (2013)
  • J.H. Yang

    Norepinephrine differentially modulates the innate inflammatory response provoked by amyloid-β peptide via action at β-adrenoceptors and activation of cAMP/PKA pathway in human THP-1 macrophages

    Exp. Neurol.

    (2012)
  • J.A. Ross

    Locus coeruleus, norepinephrine and Aβ peptides in Alzheimer's disease

    Neurobiol. Stress

    (2015)
  • C-G. Gottfries

    Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT)

    Neurobiol. Aging

    (1984)
  • A.M. Palmer

    Monoaminergic innervation of the frontal and temporal lobes in Alzheimer's disease

    Brain Res.

    (1987)
  • K.J. Reinikainen

    A post-mortem study of noradrenergic, serotonergic and GABAergic neurons in Alzheimer's disease

    J. Neurol. Sci.

    (1988)
  • R. Kaddurah-Daouk

    Metabolomic changes in autopsy-confirmed Alzheimer's disease

    Alzheimers Dement.

    (2011)
  • L.Y. Wang

    Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span

    Neurobiol. Aging

    (2013)
  • H. Reiber

    Flow rate of cerebrospinal fluid (CSF) – a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases

    J. Neurol. Sci.

    (1994)
  • R.A. Avery

    The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task

    Neuropsychopharmacology

    (2000)
  • S. Bouret et al.

    Network reset: a simplified overarching theory of locus coeruleus noradrenaline function

    Trends Neurosci.

    (2005)
  • S.K. Segal

    Norepinephrine-mediated emotional arousal facilitates subsequent pattern separation

    Neurobiol. Learn. Mem.

    (2012)
  • F. Naka

    An enriched environment increases noradrenaline concentration in the mouse brain

    Brain Res.

    (2002)
  • R. Galani

    The behavioral effects of enriched housing are not altered by serotonin depletion but enrichment alters hippocampal neurochemistry

    Neurobiol. Learn. Mem.

    (2007)
  • B.P. Ramos et al.

    Adrenergic pharmacology and cognition: Focus on the prefrontal cortex

    Pharmacol. Ther.

    (2007)
  • S. Ebrahimi

    Central β-adrenergic receptors play an important role in the enhancing effect of voluntary exercise on learning and memory in rat

    Behav. Brain Res.

    (2010)
  • R.C. Mohs

    Atomoxetine augmentation of cholinesterase inhibitor therapy in patients with Alzheimer disease: 6-month, randomized, double-blind, placebo-controlled, parallel-trial study

    Am. J. Geriatr. Psychiatry

    (2009)
  • G. Scullion

    Chronic treatment with the α2-adrenoceptor antagonist fluparoxan prevents age-related deficits in spatial working memory in APP× PS1 transgenic mice without altering β-amyloid plaque load or astrocytosis

    Neuropharmacology

    (2011)
  • P.A. van Dongen

    The human locus coeruleus in neurology and psychiatry: Parkinson's, Lewy body, Hallervorden–Spatz, Alzheimer's and Korsakoff's disease, (pre) senile dementia, schizophrenia, affective disorders, psychosis

    Prog. Neurobiol.

    (1981)
  • R. Pamphlett

    Uptake of environmental toxicants by the locus ceruleus: A potential trigger for neurodegenerative, demyelinating and psychiatric disorders

    Med. Hypotheses

    (2014)
  • V. Brezina

    Beyond the wiring diagram: signalling through complex neuromodulator networks

    Phil. Trans. R. Soc. B Biol. Sci.

    (2010)
  • S.J. Sara

    The locus coeruleus and noradrenergic modulation of cognition

    Nat. Rev. Neurosci.

    (2009)
  • H. Braak et al.

    Neuroanatomy and Pathology of Sporadic Alzheimer's Disease

    (2015)
  • B. Mravec

    Locus (coeruleus) minoris resistentiae in pathogenesis of Alzheimer's disease

    Curr. Alzheimer Res.

    (2014)
  • R.S. Wilson

    Neural reserve, neuronal density in the locus ceruleus, and cognitive decline

    Neurology

    (2013)
  • M.T. Heneka

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

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

    (2010)
  • D. German

    The human locus coeruleus: computer reconstruction of cellular distribution

    J. Neurosci.

    (1988)
  • J.B. Lohr et al.

    Locus ceruleus morphometry in aging and schizophrenia

    Acta Psychiatr. Scand.

    (1988)
  • N. Vijayashankar et al.

    Quantitative study of the pigmented neurons in the nuclei locus coeruleus and subcoeruleus in man as related to aging

    J. Neuropathol. Exp. Neurol.

    (1979)
  • V. Chan-Palay et al.

    Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression

    J. Comp. Neurol.

    (1989)
  • K.F. Manaye

    Locus-coeruleus cell loss in the aging human brain: A nonrandom process

    J. Comp. Neurol.

    (1995)
  • N. Kubis

    Preservation of midbrain catecholaminergic neurons in very old human subjects

    Brain

    (2000)
  • H. Braak

    Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years

    J. Neuropathol. Exp. Neurol.

    (2011)
  • P.T. Nelson

    Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature

    J. Neuropathol. Exp. Neurol.

    (2012)
  • H. Braak et al.

    Amyloid-β may be released from non-junctional varicosities of axons generated from abnormal tau-containing brainstem nuclei in sporadic Alzheimer's disease: a hypothesis

    Acta Neuropathol.

    (2013)
  • J. Takahashi

    Detection of changes in the locus coeruleus in patients with mild cognitive impairment and Alzheimer's disease: High-resolution fast spin-echo T1-weighted imaging

    Geriatr. Gerontol. Int.

    (2015)
  • Cited by (280)

    View all citing articles on Scopus
    View full text