Distinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in APP/PS1 transgenic mice.
Degeneration of locus ceruleus (LC) neurons and subsequent reduction of norepinephrine (NE) in LC projection areas represent an early pathological indicator of Alzheimer's disease (AD). In order to study the effects of NE depletion on cortical and hippocampal adrenergic system changes, LC degeneration was induced in 3-month-old APP/PS1 mice by the neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4). Dsp4 induced a widespread loss of norepinephrine transporter binding in multiple brain structures already at 4.5 months. This was accompanied by changes of α-1-, α-2-, and β-1-adreneroceptor binding sites as well as altered adrenoceptor mRNA expression. In parallel, we observed increased micro- and astrogliosis in cortical and hippocampal structures in dsp4-treated groups. In addition, the expression of the pro-inflammatory cytokines CCL2 and IL-1β were induced in both, dsp4-treated and APP/PS1-transgenic mice, whereas IL-1α was only up-regulated in dsp4-treated APP/PS1 mice. Concerning amyloid β (Aβ) deposition, we observed an elevation of Aβ1-42 levels in aged dsp4-treated APP/PS1 mice. These data support the hypothesis that LC degeneration leads to dysregulation of adrenergic receptors and exacerbation of Aβ-induced neuroinflammation, both of which are exploitable for early disease marker development.
Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Müllerstrasse 178, 13342 Berlin, Germany.
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D
Jardanhazi-Kurutz
M P
MP
Kummer
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Terwel
K
K
Vogel
A
A
Thiele
M T
MT
Heneka
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D018925:Chemokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005911:Gliosis / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011941:Receptors, Adrenergic / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D018925:Chemokines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D053764:Presenilin-1; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D009638:Norepinephrine