Anne Schaefer

Max Planck Institute for Biology of Ageing

Dr. Anne Schaefer

Principal Investigator
Director of MPI for Biology of Ageing
Head of Research Area 2

+49 221 37970 702

anne.schaefer[at]age.mpg.de

Website

lab_schaefer

Curriculum Vitae

Research Areas

Molecular and Cellular Mechanisms of Brain Longevity

The robustness of the brain and its failure during aging define the quality and duration of human life. My lab focuses on key systems that determine brain vulnerability to external perturbations. Our goal is to define mechanisms of neuronal longevity and the role of non-neuronal cells in this process.

Research Focus

Microglia (green) surveilling healthy neurons (red=neuronal nuclei) in the mouse striatum. (blue= DNA stain).

The human brain contains >80 billion neurons and a similar number of non-neuronal cells. Most of the brain cells remain functional for the entirety of life. The brain's robustness can be challenged by several key factors.

First, exacerbated generation or poor clearance of protein aggregates can cause brain damage.
Second, infectious diseases that occur at the body periphery can affect neuron function and longevity.
Third, genetic diseases that affect key cellular processes may have a particularly strong impact on neurons.

One of the key aspects of the lab is the identification of key molecular mechanisms of aggregate uptake and degradation by microglia.

Recent work from the lab identified novel mechanism of neuromodulatory- microglia activity. Identifying the nature of ligands that enable microglia-mediated neuromodulation is one of the key aims of the lab. Schaefer's lab investigates the mechanisms of "sickness behavior" associated with peripheral infections. The current hypothesis is that the response of neurons to peripheral impacts is mediated by microglia. The lab addresses the possible "imprinting" of frequent infections on microglia and neuronal functions followed by the establishment of stable brain cell circuits that support sickness and age-associated behaviors.

The brain's robustness relies on the operational capacity of the neuronal networks. It is conceivable that in order to stay operational, individual neurons within a network can periodically enter the state of metabolic dormancy and undergo a functional “reboot.” In this model, each neuronal circuit contains both metabolically active and dormant cells that cycle between two states in order to maintain the overall robustness of the circuit. We argue that alterations in this hypothetical metabolic cycle can alter neuron longevity and drive neurodegeneration. The lab aims to develop new approaches that can test the model by accessing the metabolic state of individual neurons in defined brain circuits.

If you can’t explain it simply, you do not understand it well enough.
Albert Einstein

Our Goals

Microglia (green) responding to aggregated beta-amyloid plaques (red) in the mouse cortex. (blue=DNA stain).

Our research covers a broad range of topics that include microglia-mediated control of neuronal activity, neuroprotection and clearance of protein aggregates, mechanisms of sickness behavior, metabolic and epigenetic control of neuronal fitness, and development of new technologies to study human neurodegenerative diseases in vitro.

Our goals are as follows:

Identify molecular mechanisms of aggregate uptake and degradation by microglia. We have discovered a novel mechanism of aggregate clearance that couples receptor-mediated signaling with the function of nuclear transcriptional regulators. Using in vitro and in vivo approaches, we aim to identify the operational principles of this aggregate-clearing mechanism and determine its role in neurodegeneration and aging in vivo.
We identified adenosine produced by microglia as a key neuromodulator in vivo. Our studies point to a broad usage of microglia-produced adenosine in various brain functions that change during the ageing process including sleep and cognition. We also aim to determine the nature of the neuromodulatory ligands produced by activated microglia.
The mechanism of sickness behavior following peripheral infectious diseases or trauma remains largely elusive. We aim to identify microglia that respond to peripheral viral infection and use this information to interrogate the role of disease-responding microglia in sickness behavior. We plan to determine whether chronic diseases lead to the establishment of a persistent state of sickness behavior. We hypothesize that epigenetic mechanisms are responsible fort the establishment of long-lasting microglial phenotypic states that contribute to sickness and age-associated behavioral alterations.
We aim to define the dynamics of metabolic activity of individual neurons within distinct brain areas. Our most immediate aim is to develop approaches for measuring neuronal metabolic activity in vivo at a single-cell resolution.
We plan to use microchip-based high-density neuronal arrays to develop an in vitro model of human neurodegenerative diseases. Our goals involve creating arrays that can perform simple tasks, communicate with external digital devices, and use this system to investigate factors that can support neuron robustness in response to various external perturbations

Key Publications

Paolicelli RC, Sierra A, Stevens B, Tremblay ME, Aguzzi A, Ajami B, Amit I, Audinat E, Bechmann I, Bennett M, Bennett F, Bessis A, Biber K, Bilbo S, Blurton-Jones M, Boddeke E, Brites D, Brône B, Brown GC, Butovsky O, Carson MJ, Castellano B, Colonna M, Cowley SA, Cunningham C, Davalos D, De Jager PL, de Strooper B, Denes A, Eggen BJL, Eyo U, Galea E, Garel S, Ginhoux F, Glass CK, Gokce O, Gomez-Nicola D, González B, Gordon S, Graeber MB, Greenhalgh AD, Gressens P, Greter M, Gutmann DH, Haass C, Heneka MT, Heppner FL, Hong S, Hume DA, Jung S, Kettenmann H, Kipnis J, Koyama R, Lemke G, Lynch M, Majewska A, Malcangio M, Malm T, Mancuso R, Masuda T, Matteoli M, McColl BW, Miron VE, Molofsky AV, Monje M, Mracsko E, Nadjar A, Neher JJ, Neniskyte U, Neumann H, Noda M, Peng B, Peri F, Perry VH, Popovich PG, Pridans C, Priller J, Prinz M, Ragozzino D, Ransohoff RM, Salter MW, Schaefer A, Schafer DP, Schwartz M, Simons M, Smith CJ, Streit WJ, Tay TL, Tsai LH, Verkhratsky A, von Bernhardi R, Wake H, Wittamer V, Wolf SA, Wu LJ, Wyss-Coray T. Microglia states and nomenclature: A field at its crossroads. Neuron. 2022 Nov 2;110(21):3458-3483. doi: 10.1016/j.neuron.2022.10.020. Review. PubMed PMID: 36327895.
Badimon A, Strasburger H, Ayata P, Chen X, Nair A, Ikegami A, Hwang P, Chan A, Graves S, Uweru J, Ledderose C, Kutlu M, Wheeler M, Kahan A, Ishikawa M, Wang Y, Loh Y, Jiang J, Surmeier DJ, Robson S, Junger W, Sebra R, Calipari E, Kenny P, Eyo U, Colonna M, Quintana F, Wake H, Gradinaru V, Schaefer A. (2020). Negative feedback control of neuronal activity by microglia. Nature, 2020 Oct;586(7829):417-423. doi: 10.1038/s41586-020-2777-8. Epub 2020 Sep 30. PMID: 32999463
Ayata P, Badimon A, Strasburger HJ, Duff MK, Montgomery SE, Loh YE, Ebert A, Pimenova AA, Ramirez BR, Chan AT, Sullivan JM, Purushothaman I, Scarpa JR, Goate AM, Busslinger M, Shen L, Losic B, Schaefer A. (2018). Epigenetic regulation of brain region-specific microglia clearance activity. Nature Neuroscience. 2018 Jul 23. doi: 10.1038/s41593-018-0192-3. PMID: 30038282
von Schimmelmann M, Feinberg PA, Sullivan JM, Ku SM, Badimon A, Duff MK, Wang Z, Lachmann A, Dewell S, Ma'ayan A, Han MH, Tarakhovsky A, Schaefer A. Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Nature Neuroscience. 2016 Oct;19(10):1321-30. doi: 10.1038/nn.4360. Epub 2016 Aug. 15. PMID: 27526204
Tan CL, Plotkin JL, Venø MT, von Schimmelmann M, Feinberg P, Mann S, Handler A, Kjems J, Surmeier DJ, O'Carroll D, Greengard P, Schaefer A.MicroRNA-128 governs neuronal excitability and motor behavior in mice.Science. 2013 December; 342 (6163):1254-8. PMID: 24311694