When Coeruleus Fibers Go, the Nose Knows It Might Be Alzheimer’s

Many people with Alzheimer’s notice their sense of smell isn’t as sharp as it used to be long before their memory declines. The underlying mechanisms responsible for this change have remained a mystery. Now, an August 8 Nature Communications study connects the dots. Researchers led by Lars Paeger and Jochen Herms at the German Center for Neurodegenerative Diseases and the Ludwig-Maximilians University Munich, Germany, discovered that the tiny but mighty brainstem structure locus coeruleus (LC) loses nerve connections to the olfactory bulb—the brain’s smell-processing center—early during Alzheimer’s. This degeneration precedes plaque deposition and is driven by microglia.

  • Locus coeruleus nerves to the olfactory bulb vanish early in AD mice.
  • Fiber loss leads to olfactory deficiency.
  • Microglia remove axons after detecting phosphatidylserine “eat me” signal.

“This elegant study represents a major advance in the field, as it is the first to identify the olfactory bulb as a region of selectively vulnerable LC axon degeneration that has functional consequences,” wrote David Weinshenker of Emory School of Medicine in Atlanta.

First author Carolin Meyer and colleagues began their investigation of olfactory dysfunction in the AppNL-G-F mice, which have three AD-associated mutations knocked into them but are free of overexpression artifacts that plague earlier transgenic models. Earlier studies had shown that these mice lose most LC axons later in the disease process (Sakakibara et al., 2021). Here, the authors looked earlier and found a 14 percent loss of noradrenergic LC fibers in the olfactory bulb at 2 months of age, rising to 27 percent and 33 percent at 3 and 6 months, respectively (image below). Lo and behold, the number of microglia also increased early, before Aβ plaque deposition.

Going Poof. LC axons (magenta) are abundant in wild-type mice (top) but thin out in APP knockout mice (middle) between 2 to 6 months old (left to right). Microglia (green, bottom images) increase prior to Aβ plaques (red), at 6 months. [Courtesy of Meyer et al., Nature Communications, 2025.]

Did the mice’s ability to smell things wane along with these fibers? In short, yes. Starting at 3 months, the APP knock-in mice took 60 percent longer to find buried food and spent less time investigating new odors than did control mice. The researchers used a cranial window in behaving mice to image the response of olfactory bulb neurons to odor stimuli using acousto-optical two-photon microscopy. Imaging showed decreased noradrenaline release in response to odor stimuli in APP knock-in mice compared to wild-type. These data represent the earliest disease-associated changes described thus far in these mice.

The researchers counted neuron numbers in the locus coeruleus at 12 months of age, to eliminate the possibility that neuron death in the LC might account for this effect. The number of LC neurons were comparable in APP knock-in and healthy mice. In fact, the damage to LC fiber projects was entirely independent of plaques.

Suspecting that microglia might have something to do with this, the scientists sequenced RNA from the mice’s olfactory bulb at 2 months of age. Two-month-old APP knock-in mice had more microglia and 2,344 differentially expressed genes. The authors wondered if these genes could be related to the unique disease-associated microglia (DAM) gene signature others had found in AD mice (Keren-Shaul et al., 2017; Monasor et al., 2020). They therefore compared their data to RNA data previously collected from 8-month-old APP knock-in mice (Sobue et al., 2021). Of the genes shared between datasets, relatively more were involved in phagocytosis and synaptic function.

The data were pointing to a problem with microglial phagocytosis. To find out, the team isolated primary olfactory bulb microglia from 2-month-old wild-type and APP knock-in mice and tested their phagocytic ability in culture. The microglia from APP knock-in mice had a 33 percent increase in phagocytosis compared to wild-type. When they imaged co-cultured LC fibers and microglia together, they spotted more lysosome activity and axon fragments within the lysosomes of AD microglia (image below).

Hungry or Hangry? Microglia (green) from APP knock-in mice (bottom) contained more lysosomes (CD68, blue) and axon fiber pieces (magenta) than wild-type mice (top). [Courtesy of Meyer et al., Nature Communications, 2025.]

After seeing phagocytosis rev up, the authors wondered if dampening it could save olfactory bulb noradrenergic fibers. To test this, they crossed APP knock-in mice with mice that lacked a key protein for microglial phagocytosis, translocator protein 18 kDa (TSPO). Not only did this slow down phagocytosis, it also increased survival of LC-olfactory bulb axons compared to APP knock-in mice with intact TSPO. What’s more, saving these axons kept mice sniffing around and finding their food as quickly as wild-type mice did.

Why might overactive microglia be targeting axons? The search was on for potential “find me” signals tagging those axons. The usual suspects, such as complement components, did not differ between the groups. However, the cell membrane component phosphatidylserine has been implicated in synapse loss in AD mouse models (Tzioras et al., 2023; Rueda-Carrasco et al., 2023). Not only did phosphatidylserine levels go up on LC axons, but the adaptor protein MFG-E8, which helps microglia bind phosphatidylserine, rose on those LC axons as well (image below). Mechanistically, overexcited neurons in APP knock-in mice flipped phosphatidylserine, so it faced the axons’ outside. This recruited more microglia to remove the dysfunctional LC axons in the mice’s olfactory bulb.

Soyon Hong and Dimitra Sokolova of University College London found this exciting, “This is in line with our recent work demonstrating that astrocyte-derived MFG-E8 instructs microglia-mediated synapse engulfment prior to Aβ plaque formation in the APPNL-F knock-in model (Sokolova et al., 2024), suggesting the phosphatidylserine ‘eat me’ signal is likely shaped by synapse type, brain region, and disease context.”

See the MFG? A three-dimensional reconstruction shows more of the MFG-E8 adaptor protein (cyan dots) on LC axons (magenta) in AD mice (right) than wild-type (left). [Courtesy of Meyer et al., Nature Communications, 2025.]

To start to see if their findings are relevant in people, the researchers first imaged microglia in 46 AD patients by way of TSPO-PET. They saw increased TSPO in the olfactory bulbs of people with prodromal AD, suggesting microglia were present in greater numbers (image below). This was accompanied by a trend toward olfactory decline, which worsened along with the person’s worsening AD. First author Meyer noted, “Drugs like lecanemab are most effective during early stage AD, and a smell test could be a valuable screening tool for older people (Jun 2025 news).”

Microglia Moving In. TSPO-PET of humans (left) and mice (right) shows increased microglia in the olfactory bulb (red ovals) in AD compared to healthy controls. [Courtesy of Meyer et al., Nature Communications, 2025.]

“These insights strengthen the view that microglia are active mediators of early synaptic change in AD rather than passive bystanders,” wrote Hong and Sokolova, “Dissecting these mechanisms will be key to devising strategies that protect synapses and slow neurodegeneration.” Weinshenker agrees, writing, “It lays the foundation for leveraging the relationship between LC axon integrity and hyposmia for early AD diagnosis and supports the development of LC/NE-targeted therapeutics.”—Sara A.M. Holec

Sara Holec is a scientist in Fort Collins, Colorado. 

Comments

  1. The locus coeruleus, the main source of the neurotransmitter norepinephrine in the brain, is affected early in Alzheimer’s disease, being the first brain region to accumulate hyperphosphorylated tau and undergoing progressive degeneration over the course of the disease (Braak et al., 2011; Theofilas et al., 2017; Weinshenker, 2018). Evidence indicates that LC degeneration occurs retrogradely, with axons dying back prior to frank cell body death, but the underlying mechanisms have not been identified. The LC is a key regulator of attention, arousal, mood, and stress responses, and both animal model and clinical data support the idea that LC dysfunction contributes to non-cognitive symptoms in prodromal AD such as anxiety, depression, and sleep disturbances. Although LC-NE neurons innervate the olfactory system and regulate olfactory function, deficits in olfactory processing common in early AD that occur long before the onset of cognitive impairment have received much less attention. In this new study, Lars Paeger’s lab addressed the aforementioned unresolved issues concerning the LC using a mouse model of AD as well as postmortem human brain tissue: namely, the integrity of the LC axons projecting to the olfactory bulb (OB), the functional consequences of their loss, and the mechanism underlying their demise.

    It had previously been shown that neurotoxic lesioning of all LC axons throughout the brain exacerbated olfactory deficits in amyloid-producing APP/PS1 transgenic mice (Rey et al., 2012), while viral-mediated overexpression of pseudophosphorylated tau in the LC impaired olfactory discrimination learning (Ghosh et al., 2019). The Paeger team noticed that LC axons in the OB degenerate in young adult (2 months old) AppNL-G-F transgenic mice, a time when LC axons in other brain regions remain intact. Combining genetically encoded NE sensors and tests in which mice need to use their sense of smell to find a buried food pellet or detect low concentrations of vanilla scent, the Paeger team observed significant deficits in odor-evoked NE release and behavioral performance AppNL-G-F compared to wild-type (WT) controls.

    Next, the authors explored the mechanisms responsible for the early LC axon degeneration in the OB. They focused on the potential role of microglia, which are capable of synapse engulfment and are abnormally activated in AD (Valiukas et al., 2025). At the time of LC axon degeneration in the OB, the number of local microglia and their expression of phagocytotic and synaptic genes were increased compared to controls as shown by immunohistochemistry and RNA sequencing. Isolated OB microglia from AppNL-G-F mice were better at engulfing synaptic material in vitro, and high-resolution three-dimensional imaging of OB sections revealed increased LC axon components inside of microglia. Knocking out the gene encoding TSPO, a protein crucial for microglia phagocytosis, preserved LC axons in the OB and rescued behavior in the buried food pellet test in AppNL-G-F mice, establishing causal relationships between microglial engulfment, LC axon loss, and olfactory function.

    But why do microglia phagocytose LC axons in the OB of the mutant mice? Further experiments showed that these axons excessively externalize phosphatidylserine, which serves as an “eat me” signal for microglia, due to LC hyperactivity, which is a canonical early adaptive response of these neurons to neurotoxic insults including AD-like pathology (Weinshenker, 2018; Kelly et al., 2021; Kelberman et al., 2023). Importantly, most of the OB phenotypes observed in AppNL-G-F mice, which express mutant APP all over the brain, were recapitulated following viral-mediated expression that was restricted to the LC.

    Noting that both hyposmia and loss of LC integrity are predictors of cognitive decline in humans, the research team examined postmortem brain samples from clinical AD cases. They found that in early stage AD prior to cognitive impairment (Thal phase 1-2, Braak stage 1-2), there was a pronounced degeneration of LC fibers in the OB, accompanied by increased expression of TSPO using PET imaging in the OB of a separate group of early AD patients.

    This elegant study represents a major advance in the field. It is the first to identify the OB as a region of selectively vulnerable LC axon degeneration that has functional consequences, and it establishes abnormal TSPO-mediated microglial phagocytosis as the culprit. This study lays the foundation for leveraging the relationship between LC axon integrity and hyposmia for early AD diagnosis and supports the development of LC/NE-targeted therapeutics such as the NE reuptake inhibitor atomoxetine, which showed promise in a recent clinical trial (Levey et al., 2022; Dammer et al., 2024).

    This paper by Meyer et al. also raises additional questions for future investigation. Given that most LC neurons appear to be hyperactive in early AD, it is not clear why the axons in the OB are more vulnerable than those in other brain regions. Indeed, hyperexcitability is a common feature of multiple circuits in early AD, yet those other neurons remain I ntact when the LC is already starting to degenerate. Do their axons not also externalize PS and attract hungry microglia? Also, the mouse model used was amyloid-based, while the main LC pathology in early AD is hyperphosphorylated tau. It will be interesting to examine olfactory behavior and LC axon integrity in the OB of mice expressing phospho-tau (or phospho-tau + beta-amyloid) in these neurons.

    References:

    Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. PubMed.

    Theofilas P, Ehrenberg AJ, Dunlop S, Di Lorenzo Alho AT, Nguy A, Leite RE, Rodriguez RD, Mejia MB, Suemoto CK, Ferretti-Rebustini RE, Polichiso L, Nascimento CF, Seeley WW, Nitrini R, Pasqualucci CA, Jacob Filho W, Rueb U, Neuhaus J, Heinsen H, Grinberg LT. Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 2016 Aug 8; PubMed.

    Weinshenker D. Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease. Trends Neurosci. 2018 Apr;41(4):211-223. Epub 2018 Feb 20 PubMed.

    Rey NL, Jardanhazi-Kurutz D, Terwel D, Kummer MP, Jourdan F, Didier A, Heneka MT. Locus coeruleus degeneration exacerbates olfactory deficits in APP/PS1 transgenic mice. Neurobiol Aging. 2012 Feb;33(2):426.e1-11. PubMed.

    Ghosh A, Torraville SE, Mukherjee B, Walling SG, Martin GM, Harley CW, Yuan Q. An experimental model of Braak's pretangle proposal for the origin of Alzheimer's disease: the role of locus coeruleus in early symptom development. Alzheimers Res Ther. 2019 Jul 3;11(1):59. PubMed.

    Valiukas Z, Tangalakis K, Apostolopoulos V, Feehan J. Microglial activation states and their implications for Alzheimer's Disease. J Prev Alzheimers Dis. 2025 Jan;12(1):100013. Epub 2025 Jan 1 PubMed.

    Kelly L, Seifi M, Ma R, Mitchell SJ, Rudolph U, Viola KL, Klein WL, Lambert JJ, Swinny JD. Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer's patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability. Neuropathol Appl Neurobiol. 2020 Oct 29; PubMed.

    Kelberman MA, Rorabaugh JM, Anderson CR, Marriott A, DePuy SD, Rasmussen K, McCann KE, Weiss JM, Weinshenker D. Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease. Neurobiol Aging. 2023 May;125:98-108. Epub 2023 Feb 1 PubMed.

    Levey AI, Qiu D, Zhao L, Hu WT, Duong DM, Higginbotham L, Dammer EB, Seyfried NT, Wingo TS, Hales CM, Gámez Tansey M, Goldstein DS, Abrol A, Calhoun VD, Goldstein FC, Hajjar I, Fagan AM, Galasko D, Edland SD, Hanfelt J, Lah JJ, Weinshenker D. A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment. Brain. 2021 Dec 17; PubMed.

    Dammer EB, Shantaraman A, Ping L, Duong DM, Gerasimov ES, Ravindran SP, Gudmundsdottir V, Frick EA, Gomez GT, Walker KA, Emilsson V, Jennings LL, Gudnason V, Western D, Cruchaga C, Lah JJ, Wingo TS, Wingo AP, Seyfried NT, Levey AI, Johnson EC. Proteomic analysis of Alzheimer's disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment. Sci Transl Med. 2024 Jun 26;16(753):eadn3504. PubMed.

    View all comments by David Weinshenker

  2. Meyer et al. elegantly demonstrate that microglia influence neuronal circuitry in the olfactory bulb during the earliest stages of Aβ pathogenesis. Microglia play a central role in sculpting synaptic connectivity across lifespan, adjusting their actions to local needs through distinct neuro-glia signaling pathways. Spatiotemporal context is therefore key to understanding which mechanisms are engaged at a given time and place. Previous studies have shown that microglia support OB development and adult-born neuron integration (Reshef et al., 2017; Wallace et al., 2020) and can remove synapses via recognition of externalized phosphatidylserine (PtdSer) (Kurematsu et al., 2022). The present work now places these processes in a disease-relevant context.

    The findings reported here are consistent with a growing body of evidence that microglia mediate compartment-specific synaptic and axonal engulfment. This is particularly relevant for AD, in which synapse loss is an early hallmark, first described in seminal work by Bob Terry, Steve DeKosky, and colleagues, and can precede neuronal death (Selkoe, 2002). Our own studies (Hong et al., 2016) and those of others have shown that microglia-synapse interactions become perturbed early and mediate synapse loss, engaging multiple pathways including complement (C1q, C3, MAC), TREM2, CX3CR1, SPP1, among others.

    A major open question has since been which molecular cues specify the synapses being targeted for removal. In AD, damaged and/or dysfunctional synaptic compartments (e.g., dendritic spines) can display apoptotic-like signals (in absence of somatic apoptosis), a process termed "synaptosis." One of the first studies was by Mattson et al., 1998; also see works by D’Amelio et al., 2011; Park et al., 2020. In the immune system, PtdSer is a canonical "eat me" cue on apoptotic cells, enabling macrophage recognition and clearance. Similarly, elegant studies in development (Scott-Hewitt et al., 2020; Li et al., 2021; Park et al., 2021) demonstrated that PtdSer is locally and dynamically externalized at synapses for glial recognition. We extended this to Aβ challenge models, showing that dysfunctional spines externalize PtdSer, leading to microglial removal (Rueda-Carrasco et al., 2023). The current work by Meyer et al. strengthens the case for PtdSer as a molecular cue on neuronal compartments for microglia.

    It is well established that PtdSer is recognized by a range of phagocytic receptors, including TREM2, MERTK, GPR56, MFGE8, among others (Lemke, 2019)—through both direct and indirect (bridging) interactions. In our work (Rueda-Carrasco et al., 2023), we found that functional TREM2 is critical for selective engulfment of PtdSer+ spines. The current study highlights MFG-E8, a bifunctional linker between PtdSer and phagocytic receptors (Hanayama et al., 2002), echoing findings in human cells (Tzioras et al., 2023). This is in line with our recent unpublished work (Sokolova et al., 2024), which mechanistically dissects how MFG-E8 mediates synapse loss in the less-aggressive hAPP-NL-F knock-in model, demonstrating that astrocyte-derived MFG-E8 instructs microglia-mediated synapse engulfment prior to Aβ plaque formation. Together, these studies highlight PtdSer as a synaptic "eat me" signal, with the choice of downstream phagocytic receptors likely shaped by synapse type, brain region, and disease context (Sokolova et al., 2021).

    These insights strengthen the view that microglia are active mediators of early synaptic change in AD rather than passive bystanders. The pressing challenge is to define how pathways essential for healthy synaptic maintenance are co-opted into maladaptive roles in disease, and how the surrounding cellular environment shapes this shift. Dissecting these mechanisms will be key to devising strategies that protect synapses and slow neurodegeneration.

    —Dimitra Sokolova, University College London, is a co-author of this comment.

    References:

    Reshef R, Kudryavitskaya E, Shani-Narkiss H, Isaacson B, Rimmerman N, Mizrahi A, Yirmiya R. The role of microglia and their CX3CR1 signaling in adult neurogenesis in the olfactory bulb. Elife. 2017 Dec 18;6 PubMed.

    Wallace J, Lord J, Dissing-Olesen L, Stevens B, Murthy VN. Microglial depletion disrupts normal functional development of adult-born neurons in the olfactory bulb. Elife. 2020 Mar 9;9 PubMed.

    Kurematsu C, Sawada M, Ohmuraya M, Tanaka M, Kuboyama K, Ogino T, Matsumoto M, Oishi H, Inada H, Ishido Y, Sakakibara Y, Nguyen HB, Thai TQ, Kohsaka S, Ohno N, Yamada MK, Asai M, Sokabe M, Nabekura J, Asano K, Tanaka M, Sawamoto K. Synaptic pruning of murine adult-born neurons by microglia depends on phosphatidylserine. J Exp Med. 2022 Apr 4;219(4) Epub 2022 Mar 17 PubMed.

    Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002 Oct 25;298(5594):789-91. PubMed.

    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.

    Mattson MP, Partin J, Begley JG. Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites. Brain Res. 1998 Oct 5;807(1-2):167-76. PubMed.

    D'Amelio M, Cavallucci V, Middei S, Marchetti C, Pacioni S, Ferri A, Diamantini A, De Zio D, Carrara P, Battistini L, Moreno S, Bacci A, Ammassari-Teule M, Marie H, Cecconi F. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nat Neurosci. 2011 Jan;14(1):69-76. PubMed.

    Park G, Nhan HS, Tyan SH, Kawakatsu Y, Zhang C, Navarro M, Koo EH. Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid β-Protein-Induced Synapse Loss in Alzheimer's Disease. Cell Rep. 2020 Jun 30;31(13):107839. PubMed.

    Scott-Hewitt N, Perrucci F, Morini R, Erreni M, Mahoney M, Witkowska A, Carey A, Faggiani E, Schuetz LT, Mason S, Tamborini M, Bizzotto M, Passoni L, Filipello F, Jahn R, Stevens B, Matteoli M. Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia. EMBO J. 2020 Aug 17;39(16):e105380. Epub 2020 Jul 13 PubMed.

    Li T, Yu D, Oak HC, Zhu B, Wang L, Jiang X, Molday RS, Kriegstein A, Piao X. Phospholipid-flippase chaperone CDC50A is required for synapse maintenance by regulating phosphatidylserine exposure. EMBO J. 2021 Nov 2;40(21):e107915. Epub 2021 Sep 29 PubMed.

    Park J, Choi Y, Jung E, Lee SH, Sohn JW, Chung WS. Microglial MERTK eliminates phosphatidylserine-displaying inhibitory post-synapses. EMBO J. 2021 Aug 2;40(15):e107121. Epub 2021 May 19 PubMed.

    Lemke G. How macrophages deal with death. Nat Rev Immunol. 2019 Sep;19(9):539-549. PubMed.

    Rueda-Carrasco J, Sokolova D, Lee SE, Childs T, Jurčáková N, Crowley G, De Schepper S, Ge JZ, Lachica JI, Toomey CE, Freeman OJ, Hardy J, Barnes SJ, Lashley T, Stevens B, Chang S, Hong S. Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models. EMBO J. 2023 Oct 4;42(19):e113246. Epub 2023 Aug 14 PubMed. Correction.

    Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002 May 9;417(6885):182-7. PubMed.

    Tzioras M, Daniels MJ, Davies C, Baxter P, King D, McKay S, Varga B, Popovic K, Hernandez M, Stevenson AJ, Barrington J, Drinkwater E, Borella J, Holloway RK, Tulloch J, Moss J, Latta C, Kandasamy J, Sokol D, Smith C, Miron VE, Káradóttir RT, Hardingham GE, Henstridge CM, Brennan PM, McColl BW, Spires-Jones TL. Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8. Cell Rep Med. 2023 Sep 19;4(9):101175. Epub 2023 Aug 30 PubMed.

    Sokolova D, Ghansah SA, Puletti F, Georgiades T, De Schepper S, Zheng Y, Crowley G, Wu L, Rueda-Carrasco J, Koutsiouroumpa A, Muckett P, Freeman OJ, Khakh BS, Hong S. Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models. bioRxiv. 2024 Dec 30; PubMed.

    Sokolova D, Childs T, Hong S. Insight into the role of phosphatidylserine in complement-mediated synapse loss in Alzheimer's disease. Fac Rev. 2021;10:19. Epub 2021 Feb 24 PubMed.

    View all comments by Soyon Hong

  3. One of the earliest symptoms of Alzheimer's disease are olfactory deficits. We wanted to understand why this happens, especially since antibody therapies such as lecanemab are most effective when the disease is detected at an early stage. Therefore, we focused on the biological mechanism behind olfactory dysfunction. Using a mouse model of Alzheimer’s disease, we discovered that the locus coeruleus-noradrenergic system degenerates early in the olfactory bulb and that this “damage” is caused by microglia. Simple smell tests could become a valuable screening tool for older people, helping to identify those at risk of Alzheimer's disease at an earlier stage and enabling earlier treatment.

    View all comments by Carolin Meyer

Make a Comment

To make a comment you must login or register.

References

Research Models Citations

  1. APP NL-G-F Knock-in

Therapeutics Citations

  1. Leqembi

News Citations

  1. Sniffing Out Early Signs of Parkinson’s Disease

Paper Citations

  1. Sakakibara Y, Hirota Y, Ibaraki K, Takei K, Chikamatsu S, Tsubokawa Y, Saito T, Saido TC, Sekiya M, Iijima KM. Widespread Reduced Density of Noradrenergic Locus Coeruleus Axons in the App Knock-In Mouse Model of Amyloid-β Amyloidosis. J Alzheimers Dis. 2021;82(4):1513-1530. PubMed.
  2. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.
  3. Sebastian Monasor L, Müller SA, Colombo AV, Tanrioever G, König J, Roth S, Liesz A, Berghofer A, Piechotta A, Prestel M, Saito T, Saido TC, Herms J, Willem M, Haass C, Lichtenthaler SF, Tahirovic S. Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models. Elife. 2020 Jun 8;9 PubMed.
  4. Sobue A, Komine O, Hara Y, Endo F, Mizoguchi H, Watanabe S, Murayama S, Saito T, Saido TC, Sahara N, Higuchi M, Ogi T, Yamanaka K. Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease. Acta Neuropathol Commun. 2021 Jan 5;9(1):1. PubMed.
  5. Tzioras M, Daniels MJ, Davies C, Baxter P, King D, McKay S, Varga B, Popovic K, Hernandez M, Stevenson AJ, Barrington J, Drinkwater E, Borella J, Holloway RK, Tulloch J, Moss J, Latta C, Kandasamy J, Sokol D, Smith C, Miron VE, Káradóttir RT, Hardingham GE, Henstridge CM, Brennan PM, McColl BW, Spires-Jones TL. Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8. Cell Rep Med. 2023 Sep 19;4(9):101175. Epub 2023 Aug 30 PubMed.
  6. Rueda-Carrasco J, Sokolova D, Lee SE, Childs T, Jurčáková N, Crowley G, De Schepper S, Ge JZ, Lachica JI, Toomey CE, Freeman OJ, Hardy J, Barnes SJ, Lashley T, Stevens B, Chang S, Hong S. Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models. EMBO J. 2023 Oct 4;42(19):e113246. Epub 2023 Aug 14 PubMed. Correction.
  7. Sokolova D, Ghansah SA, Puletti F, Georgiades T, De Schepper S, Zheng Y, Crowley G, Wu L, Rueda-Carrasco J, Koutsiouroumpa A, Muckett P, Freeman OJ, Khakh BS, Hong S. Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models. bioRxiv. 2024 Dec 30; PubMed.

External Citations

  1.  

Further Reading

Primary Papers

  1. Meyer C, Niedermeier T, Feyen PL, Strübing FL, Rauchmann BS, Karali K, Gentz J, Tillmann YE, Landgraf NF, Rumpf SL, Ochs K, Wind-Mark K, Biechele G, Wagner J, Guersel S, Kurz CI, Schweiger M, Prtvar D, Shi Y, Banati RB, Liu GJ, Middleton RJ, Mitteregger-Kretzschmar G, Perneczky R, Koeglsperger T, Neher JJ, Tahirovic S, Brendel M, Herms J, Paeger L. Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer's disease. Nat Commun. 2025 Aug 8;16(1):7338. PubMed.

Annotate

To make an annotation you must Login or Register.