Pesämaa I, Müller SA, Robinson S, Darcher A, Paquet D, Zetterberg H, Lichtenthaler SF, Haass C. A MICROGLIAL ACTIVITY STATE BIOMARKER PANEL DIFFERENTIATES FTD-GRANULIN AND ALZHEIMER'S DISEASE PATIENTS FROM CONTROLS. bioRxiv. 2023 Jun 16; PubMed.

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  1. As we enter the age of plausible microglia-targeted therapeutics, it is essential that relevant biomarkers, applicable across neurodegenerative diseases, be identified.

    Positron emission tomography (PET) studies with tracers targeting the TSPO protein have characterized neuroinflammation as a common feature across these diseases, and as a key player in defining prognosis and disease progression in both frontotemporal dementia and Alzheimer’s disease (Malpetti et al., 2020; Pascoal et al., 2021; Malpetti et al., 2023). However, TSPO PET currently cannot distinguish microglial phenotypes and related processes. To this end, complementary in vivo biomarkers are needed to stratify patients, to ascertain target engagement, and to monitor effects of microglia-modulating therapies that are in the development pipeline, as neuroinflammation has become a principal candidate target of AD drug development (Cummings et al., 2023).

    The effort to find such markers requires a deeply translational approach. This innovative study by Pesämaa, Haass, and colleagues provides a great example of how one can tackle biomarker development for this field and fill knowledge gaps by combining preclinical (murine and human IPSC-derived microglia) and clinical data (biospecimens from people living with dementia) in a translational workflow.

    Using this approach, the authors identify a panel of six proteins that were upregulated in the CSF of FTD progranulin mutation carriers. A subset of three of these proteins was also elevated in people with AD and mild cognitive impairment (thus able to detect early changes) and sensitive to participants’ amyloid status.

    This opens up the possibility that proteomic approaches such as this one may, when combined with complementary markers including PET, be able to focus in on microglial activation-related processes.

    Future studies will need to validate these markers across different disorders and assess whether levels of these proteins co-vary with and/or predict clinical outcome/severity. It will also be key to determine whether the CSF-based findings may translate to more readily available and scalable blood markers.

    Pesämaa, Haass, and colleagues are to be congratulated for taking a further crucial step toward novel, clinically plausible cross-diagnostic and translational microglial biomarkers.

    References:

    Cummings J, Lee G, Zhong K, Fonseca J, Taghva K. Alzheimer's disease drug development pipeline: 2021. Alzheimers Dement (N Y). 2021;7(1):e12179. Epub 2021 May 25 PubMed.

    Malpetti M, Kievit RA, Passamonti L, Jones PS, Tsvetanov KA, Rittman T, Mak E, Nicastro N, Bevan-Jones WR, Su L, Hong YT, Fryer TD, Aigbirhio FI, O'Brien JT, Rowe JB. Microglial activation and tau burden predict cognitive decline in Alzheimer's disease. Brain. 2020 May 1;143(5):1588-1602. PubMed.

    Malpetti M, Cope TE, Street D, Jones PS, Hezemans FH, Mak E, Tsvetanov KA, Rittman T, Bevan-Jones WR, Patterson K, Passamonti L, Fryer TD, Hong YT, Aigbirhio FI, O'Brien JT, Rowe JB. Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia. Brain. 2023 Aug 1;146(8):3221-3231. PubMed.

    Pascoal TA, Benedet AL, Ashton NJ, Kang MS, Therriault J, Chamoun M, Savard M, Lussier FZ, Tissot C, Karikari TK, Ottoy J, Mathotaarachchi S, Stevenson J, Massarweh G, Schöll M, de Leon MJ, Soucy JP, Edison P, Blennow K, Zetterberg H, Gauthier S, Rosa-Neto P. Microglial activation and tau propagate jointly across Braak stages. Nat Med. 2021 Sep;27(9):1592-1599. Epub 2021 Aug 26 PubMed. Correction.

    View all comments by Maura Malpetti

  2. Amid development of disease-modifying treatments for Alzheimer's disease, including emerging microglia-modulating therapies, we need to develop reliable biomarkers for evaluating microglial dynamics in humans. CSF sTREM2 has been extensively studied as a marker of the TREM2-mediated microglial response in AD and, in most studies, higher CSF sTREM2 levels have been associated with a more favorable prognosis for patients (Morenas-Rodríguez et al., 2022; Ewers et al., 2019; Suárez-Calvet et al., 2016; Pereira et al., 2022). 

    However, the microglial response to the disease is intricate and dynamic, involving various cell states. We must identify additional markers beyond sTREM2 that better reflect the diversity of the microglial response and its potential as a target for therapeutic modulation.

    In their study, Pesämaa et al. took an innovative approach by investigating two opposing microglial phenotypes. They analyzed the proteome of microglia and CSF from genetically modified mouse models lacking TREM2 (locked in a homeostatic state) and GRN (hyperactivated microglia) (Götzl et al., 2019). Additionally, they examined iPSC-derived microglia.

    The authors successfully identified specific proteins associated with opposite microglial activation states. These findings were further validated by analysing CSF from patients with frontotemporal dementia carrying GRN mutations. The authors proposed a panel of six proteins as potential indicators for microglial reactivity. Notably, three of these (FABP3, GDI1, MDH1) were capable of differentiating amyloid-positive from amyloid-negative cases with mild cognitive impairment. It is worth mentioning that some of these proteins are also implicated in lipid dysmetabolism, as genetic evidence has linked several Alzheimer's disease-associated risk loci to lipid and microglial metabolism.

    Microglial state definitions predominantly rely on transcriptomic profiling. While numerous studies have explored single glial reactivity markers in human fluids, the question arises as to whether we can establish a marker profile that accurately reflects microglial state dynamics. This study, along with a recent investigation by the BioFINDER group—which investigates a set of markers of the disease-associated microglial activation stage 2 (Pereira et al, 2022)—is paving the way for future research in glial biomarkers.

    Moving forward, it is crucial to further investigate and validate these candidate microglial biomarkers in larger, longitudinal cohorts covering the entire Alzheimer's disease continuum, as well as other neurodegenerative cohorts. Understanding the microglial states associated with better or worse prognoses could aid in the design of more effective microglial-modulating therapies. Additionally, these microglial biomarkers may hold clinical utility in monitoring therapeutic response and identifying patients who would benefit most from novel treatments targeting microglial reactivity, but also amyloid deposition.

    It is conceivable that the individual response to anti-amyloid drugs may vary depending on the predominant microglial state response exhibited by each individual.

    References:

    Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C, Alzheimer’s Disease Neuroimaging Initiative. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease. Sci Transl Med. 2019 Aug 28;11(507) PubMed.

    Götzl JK, Brendel M, Werner G, Parhizkar S, Sebastian Monasor L, Kleinberger G, Colombo AV, Deussing M, Wagner M, Winkelmann J, Diehl-Schmid J, Levin J, Fellerer K, Reifschneider A, Bultmann S, Bartenstein P, Rominger A, Tahirovic S, Smith ST, Madore C, Butovsky O, Capell A, Haass C. Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism. EMBO Mol Med. 2019 Jun;11(6) PubMed.

    Morenas-Rodríguez E, Li Y, Nuscher B, Franzmeier N, Xiong C, Suárez-Calvet M, Fagan AM, Schultz S, Gordon BA, Benzinger TL, Hassenstab J, McDade E, Feederle R, Karch CM, Schlepckow K, Morris JC, Kleinberger G, Nellgard B, Vöglein J, Blennow K, Zetterberg H, Ewers M, Jucker M, Levin J, Bateman RJ, Haass C, Dominantly Inherited Alzheimer Network. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study. Lancet Neurol. 2022 Apr;21(4):329-341. PubMed.

    Pereira JB, Janelidze S, Strandberg O, Whelan CD, Zetterberg H, Blennow K, Palmqvist S, Stomrud E, Mattsson-Carlgren N, Hansson O. Microglial activation protects against accumulation of tau aggregates in nondemented individuals with underlying Alzheimer's disease pathology. Nat Aging. 2022 Dec;2(12):1138-1144. Epub 2022 Nov 28 PubMed.

    Suárez-Calvet M, Kleinberger G, Araque Caballero MÁ, Brendel M, Rominger A, Alcolea D, Fortea J, Lleó A, Blesa R, Gispert JD, Sánchez-Valle R, Antonell A, Rami L, Molinuevo JL, Brosseron F, Traschütz A, Heneka MT, Struyfs H, Engelborghs S, Sleegers K, Van Broeckhoven C, Zetterberg H, Nellgård B, Blennow K, Crispin A, Ewers M, Haass C. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers. EMBO Mol Med. 2016 May 2;8(5):466-76. PubMed.

    View all comments by Marc Suárez-Calvet

  3. There is an urgent need to identify biomarkers associated with microglial activation in order to increase its protective mechanisms against pathology. In this study, the authors observed that GRN KO mice, which show microglial hyperactivation, present upregulation of a panel of six markers. These markers were increased in frontotemporal dementia cases and three of them—FABP3, MDH1, and GDI1—were also elevated in AD patients in response to early amyloid accumulation.

    These findings shed new light into biomarkers that can inform us about specific microglial states, which can increase their protective effects in clinical trials. Replication in other cohorts is now needed to confirm these interesting findings.

    View all comments by Joana Pereira

  4. Here, Pesämaa et al. used two different models—GRN KO mice with TREM2 KO mice, and hiMGL with GRN mutations—to identify a panel of six biomarkers for microglia activation. They then validated the upregulation of some of these biomarkers in both FTD and AD CSF. It is nice to see that markers identified in mouse models and in vitro can be validated in human patients.

    Among the six biomarkers identified, GPNMB and FABP3 had been previously identified as DAM markers in the 5XFAD model (Keren-Shaul, 2017), whereas CD44 was identified as a reactive astrocyte marker (Qian et al., 2023). hus, as the authors mention in their manuscript, the identified biomarkers are not microglia-specific, but more likely microglia activity-dependent.

    In the next steps, it would be important to correlate the biomarker levels with disease progression and pathological changes, for example, to correlate the biomarker levels with amyloid-PET or tau-PET in AD, so that the biomarkers can be used to predict disease progression and to speculate on the time window for targeting microglia therapeutically.

    References:

    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.

    Qian K, Jiang X, Liu ZQ, Zhang J, Fu P, Su Y, Brazhe NA, Liu D, Zhu LQ. Revisiting the critical roles of reactive astrocytes in neurodegeneration. Mol Psychiatry. 2023 Apr 10; PubMed.

    View all comments by Yingyue Zhou

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