Disproportionate Loss of Noradrenergic and Cholinergic Neurons as Cause of Depression in Alzheimer's Disease - A Hypothesis

Förstl, Hans; Lévy, Raymond; Burns, Alana M.; Luthert, PJ; Cairns, N

doi:10.1055/s-2007-1014267

Cited by 50 publications

(32 citation statements)

References 9 publications

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“…However, the reduction of LC neurons positively correlates with Aβ plaque density, NFT numbers, and the severity of dementia (3). Importantly, the loss of LC neurons was found to be more extensive and to correlate better with the progression of AD than the cholinergic cell loss observed in the nucleus basalis of Meynert (15,16). In contrast, compensatory mechanisms regarding NE levels in the CSF and the mRNA expression of α2-adrenoreceptors in the hippocampus of AD patients have been suggested (17)(18)(19).…”

Section: Ne Depletion Decreases Microglial Phagocytosis and Recruitmementioning

confidence: 93%

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.

423

411

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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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Section: Ne Depletion Decreases Microglial Phagocytosis and Recruitmementioning

confidence: 93%

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.

423

411

View full text Add to dashboard Cite

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“…In AD, the development of depression may be the consequence of the underlying CNS pathology, namely the selective loss of noradrenergic cells in the locus ceruleus and possibly the serotonergic raphe nuclei. [26][27][28] Functional and structural neuroimaging studies in subjects with AD have correlated the presence of depression and apathy with atrophy, hypoperfusion, and hypometabolism in the frontal cortex and anterior cingulate. [29][30][31] It is possible that depressed patients with aMCI constitute a distinct subpopulation that more often represents early stage AD and already exhibits similar pathophysiologic changes associated with AD, including those contributing to the depressive syndrome.…”

Section: Effect Of Donepezil Treatment In the Nondepressedmentioning

confidence: 99%

Donepezil delays progression to AD in MCI subjects with depressive symptoms

et al. 2009

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Objective: To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship. Methods:The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD.

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“…This subgroup may share a distinct subtype of disease; previous studies have suggested that the development of depression in dementia is associated with the degeneration of the locus ceruleus and substantia nigra. [36][37][38][39] Also, 2 conditions may share common pathways through an interaction between the hippocampus and the hypothalamicpituitary-adrenal axis. [40][41][42][43][44][45][46][47][48] Clues may emerge from trials of the effects of antidementia drugs on mood or of the effects of antidepressant drugs on cognition: studies of trichlorfon (metrifonate) and tacrine hydrochloride in AD suggest that these agents can lessen anhedonia and other symptoms of depression.…”

Section: Commentmentioning

confidence: 99%