Norepinephrine-mediated regulation of endogenous Aβ₄₂ peptide levels: effects of noradrenergic depletion and restoration

Abstract

The locus coeruleus (LC), a cluster of noradrenergic neurons in the dorsal pons, is the brain’s main source of norepinephrine (NE), crucial for memory, cognition, and stress response. NE dysregulation has been linked to mood disorders, chronic stress, and neurodegenerative diseases such as Alzheimer’s disease (AD). Amyloid-β₄₂ (Aβ₄₂) is a key protein in AD pathology, and forms plaques that trigger neurodegeneration. Studies show elevated Aβ₄₂ levels are associated with anxiety symptoms, even in cognitively normal individuals. Previous research suggests a positive correlation between NE and Aβ₄₂, with Aβ₄₂ present in NE-producing LC neurons. NE may affect Aβ₄₂ levels through adrenergic receptors on neurons or microglia. However, the exact role of NE in modulating Aβ₄₂ remains unclear. Using the NE depletion models,  N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) lesions and dopamine β-hydroxylase (DBH) knockout (KO) mice, researchers found reduced Aβ₄₂ levels without changes in amyloid precursor protein processing. A newer model, DBH internal ribosome entry site-Cre × floxed tyrosine hydroxylase (DBH-IRES-Cre × floxed-TH) preserved dopamine (DA) but eliminated NE in adrenergic neurons, further supporting the specific influence of NE on Aβ₄₂. Findings indicate that decreased Aβ₄₂ in NE-depleted mice stems not from altered DA but from NE loss. This highlights the NE-mediated regulation of endogenous Aβ₄₂ and the role of NE in AD-related pathology.

Keywords

amyloid / stress / norepinephrine / dopamine-β-hydroxylase / locus coeruleus

References

[1] Martin-Belmonte A , Aguado C , Alfaro-Ruiz R , Itakura M , Moreno-Martínez AE , de la Ossa L , Molnár E , Fukazawa Y , Luján R . Age-dependent shift of AMPA receptors from synapses to intracellular compartments in Alzheimer’s disease: immunocytochemical analysis of the CA1 hippocampal region in APP/PS1 transgenic mouse model. Front Aging Neurosci 2020; 12: 577996

[2] Selkoe DJ , Hardy J . The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016; 8(6): 595–608

[3] Bateman RJ , Xiong C , Benzinger TL , Fagan AM , Goate A , Fox NC , Marcus DS , Cairns NJ , Xie X , Blazey TM , Holtzman DM , Santacruz A , Buckles V , Oliver A , Moulder K , Aisen PS , Ghetti B , Klunk WE , McDade E , Martins RN , Masters CL , Mayeux R , Ringman JM , Rossor MN , Schofield PR , Sperling RA , Salloway S , Morris JC . Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 2012; 367(9): 795–804

[4] Braak H , Del Tredici K . The pathological process underlying Alzheimer disease in individuals under thirty. Acta Neuropathol 2011; 121(2): 171–181

[5] Zarow C , Lyness SA , Mortimer JA , Chui HC . Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 2003; 60(3): 337–341

[6] Heneka MT , Nadrigny F , Regen T , Martinez-Hernandez A , Dumitrescu-Ozimek L , Terwel D , Jardanhazi-Kurutz D , Walter J , Kirchhoff F , Hanisch UK , Kummer MP . Locus coeruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 2010; 107(13): 6058–6063

[7] Cirrito JR , Kang JE , Lee J , Stewart FR , Verges DK , Silverio LM , Bu G , Mennerick S , Holtzman DM . Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo. Neuron 2005; 48(4): 633–648

[8] Tsetsenis T , Badyna JK , Wilson JA , Zhang X , Krizman EN , Subramaniyan M , Yang K , Thomas SA , Dani JA . Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories. Proc Natl Acad Sci USA 2021; 118(40): e2111069118

[9] Thomas SA , Matsumoto AM , Palmiter RD . Noradrenaline is essential for mouse fetal development. Nature 1995; 374(6523): 643–646

[10] Xu F , Gainetdinov RR , Wetsel WC , Jones SR , Bohn LM , Miller GW , Wang YM , Caron MG . Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci 2000; 3(5): 465–471

[11] Kalinin S , Gavrilyuk V , Polak PE , Vasser R , Zhao J , Heneka MT , Feinstein DL . Noradrenaline deficiency in brain increases β-amyloid plaque burden in an animal model of Alzheimer’s disease. Neurobiol Aging 2007; 28(8): 1206–1214

[12] Nakagawa Y , Yamada S . The relationships among metal homeostasis, mitochondria, and locus coeruleus in psychiatric and neurodegenerative disorders: potential pathogenetic mechanism and therapeutic implications. Cell Mol Neurobiol 2023; 43(3): 963–989

[13] Wilson RS , Arnold SE , Schneider JA , Li Y , Bennett DA . Chronic distress, age-related neuropathology, and late-life dementia. Psychosom Med 2007; 69(1): 47–53

[14] Xie L , Kang H , Xu Q , Chen MJ , Liao Y , Thiyagarajan M , O’Donnell J , Christensen DJ , Nicholson C , Iliff JJ , Takano T , Deane R , Nedergaard M . Sleep drives metabolite clearance from the adult brain. Science 2013; 342(6156): 373–377

[15] McEwen BS . Physiology and neurobiology of stress and adaptation: the central role of the brain. Physiol Rev 2007; 87(3): 873–904

RIGHTS & PERMISSIONS

Higher Education Press