Best Paper Award

T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis

Age-related brain damage induces inflammation and is a major risk factor for
neurodegenerative diseases including Alzheimer’s disease (AD). Over the past few decades,
despite remarkable progress in understanding how neurons and glial cells such as microglia and
astrocytes drive pathology, oligodendrocytes remain understudied. Oligodendrocyte pathology
has been shown in both patients and AD mouse models, but it remains unknown how these
alterations drive the development of the disease.
Using mouse models of AD, we observed increased myelin abnormalities and oligodendrocyte
damage in both the white and grey matter. Interestingly, we observed that this oligodendrocyte
pathology was accompanied with increased infiltration of CD8+ T cells. To understand the
mechanism, we depleted CD8+ T cells by administrating neutralizing antibodies. This treatment
improved learning and spatial memory, reduced inflammation and rescued myelin integrity and
oligodendrocyte health. But how do CD8+ T-cells induce oligodendrocyte pathology? To
answer this, we used single cell RNA sequencing and spatial transcriptomics to identify a
microglia sub-cluster in direct vicinity of T cells, expressing major histocompatibility complex
II genes. In an ex vivo setting, we showed that these abnormally activated microglia displayed
myelin damaging activity including increased phagocytosis of myelin fibers.
Overall, our study characterizes oligodendrocyte and myelin damage in AD and highlights how
CD8+ T cells can abnormally activate microglia to damage myelin. Furthermore, this
progressive myelin damage acts like a self-propelling positive feedback system, wherein more
myelin pathology induces even more inflammation. This study along with other recent work
hints that oligodendrocytes are not passive elements but rather dynamic facilitators to the
progression of the disease. Furthermore, therapeutic strategies targeting inflammation to
improve oligodendrocyte and myelin health can be promising to delay AD pathology

Clinical Outcomes and Cost-Effectiveness of Collaborative Dementia Care
A Secondary Analysis of a Cluster Randomized Clinical Trial

Bernhard Michalowsky

This secondary analysis of a German cluster-randomized clinical trial (DelpHi-MV) evaluated the long-term clinical outcomes and cost-effectiveness of collaborative dementia care management compared with usual care over 36 months. The care model was based on a structured six-month intervention led by specifically qualified nurses, who assessed patients‘ individual unmet needs and provided tailored support in close collaboration with various healthcare stakeholders.

The findings demonstrated that the collaborative care model produced sustained clinical benefits well beyond the intervention period. Patients receiving support had significantly fewer behavioural and psychological symptoms (measured by the NPI), indicating reduced agitation, mood disturbances, and related challenges and reported significantly better mental health (SF-12 mental component scores). Their caregivers experienced substantially lower caregiver burden (BIZA-D) 36 months after baseline. However, there was no significant effect on physical health, overall health-related quality of life, use of anti-dementia drugs, or reduction in potentially inappropriate medications.

From an economic perspective, patients receiving the collaborative care model gained 0.137 quality-adjusted life years (QALYs) over 36 months, with only a marginal, nonsignificant increase in healthcare costs, resulting in an incremental cost-effectiveness ratio of € 3,186 per QALY gained, which is highly favourable by common cost-effectiveness thresholds. Notably, the model of collaborative care was highly effective and efficient for those living alone.

Overall, the study provides robust evidence that models of collaborative care deliver long-term improvements in patient well-being, reduce caregiver stress, and are cost-effective. Therefore, the study results will support the translation of this care model into routine care practice, given its sustained impact on patients, caregivers, and health systems.

Comparing two caregiver-delivered music listening interventions for community-dwelling people with dementia: A randomised controlled crossover pilot trial

Short Paper Summary Lena Hofbauer: Comparing two caregiver-delivered music listening interventions for community-dwelling people with dementia: A randomised controlled crossover pilot trial

This research paper investigated the effects of (1) fast music with a positive emotional tone and (2) slow music with a positive emotional tone on people living with dementia at home. The aim was to determine whether music-based interventions, delivered by informal caregivers, could support cognition and well-being in everyday settings.

The results showed that listening to fast, positive music led to significantly better memory performance, specifically in delayed recall, compared to slow, positive music. This suggests that fast, positive music may have a stimulating effect on cognitive function in people with dementia.

In addition to measurable memory improvements, caregivers observed that fast music often boosted mood at the time of listening and encouraged physical engagement, such as clapping and moving to the beat. In contrast, listening to slow music was more associated with relaxation and calmness. While it did not show the same cognitive benefits as the faster music, it created soothing moments for the person with dementia. Importantly, both types of music were reported to have immediate, in-the-moment effects that enhanced well-being, even if only temporarily.

Overall, this research paper highlights the potential of music listening – particularly fast, positive music – as a simple, home-based tool to support cognitive health and emotional connection in people with dementia. The findings underscore music’s value not only as entertainment but as a meaningful part of dementia care at home.

„NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer’s disease progression“

(in: Immunity, 2025)

Alzheimer’s disease is associated with the deposition of a protein called amyloid-beta in the brain. The aggregation of this protein gives rise to a chain of events, that ultimately harm neurons and lead to their death, which causes cognitive changes and memory loss that leads to Alzheimer’s disease. Alzheimer’s disease involves a complex interaction of different mechanisms, including neuroinflammation. In our laboratory, we examine the role of neuroinflammation in the development of Alzheimer’s disease and dementia, and test different ways to prevent inflammation occurring in the brain. In our paper that was recently published, we specifically inhibited a molecular complex called the NLRP3 inflammasome. It is found in microglia, which are the immune cells of the brain.

The NLRP3 inflammasome is like an alarm bell. In Alzheimer’s disease, its activation triggers an inflammatory response that harms various brain cells including neurons. For this reason, researchers have been exploring ways to inactivate the NLRP3 inflammasome using pharmacological inhibitors. We were able to confirm previous findings that inhibiting NLRP3 reduces neuroinflammation in models of Alzheimer’s disease. However, we were also able to show for the first time that preventing NLRP3 from signaling helped microglia to clear the harmful amyloid-beta deposits that build up during Alzheimer’s disease, using a process called phagocytosis. The novelty of our findings is that they provide a better understanding of the important role that NLRP3 plays in microglia and we also unraveled the mechanism behind why its inhibition is so beneficial in models of Alzheimer’s disease. In our pre-clinical studies, we identified previously unknown signaling pathways that are influenced by NLRP3. In particular, we found that NLRP3 regulates how microglia use nutrients and how these nutrients act on select genes that have a major impact on the function of microglia. These pathways are very important for the ability of microglia to perform phagocytosis and clear amyloid-deposits. As we could show that NLRP3 can control these pathways consistently across multiple models of disease, these findings could help in the development of therapies for dementia. Together our research shows that NLRP3 is a promising target for the treatment of Alzheimer’s disease.

Title of the publication

„Reactivated endogenous retroviruses promote protein aggregate spreading.“
in: Nat Commun. 2023 Aug 18; 14(1):5034. doi: 10.1038/s41467-023-40632-z. PMID: 37596282

Short summary of the paper

Our recent study reveals a potential link between the reactivation of endogenous retroviruses (ERVs) and the progression of neurodegenerative diseases like Alzheimer’s disease. ERVs are remnants of ancient viral infections embedded in our DNA, which are typically inactive, but become reactivated in neurodegenerative diseases. Our research demonstrates that once reactivated, ERVs promote the spreading of protein aggregates, such as Tau, between cells, accelerating disease progression.

The spread of protein aggregates follow a prion-like mechanism, where small seeds of misfolded proteins transfer between cells, fueling further misfolding and contributing to the degeneration seen in Alzheimer’s. ERVs enhance this process through viral envelope proteins, which promote direct cell-to-cell interactions and the uptake and cytosolic release of harmful protein aggregates. Interestingly, viral envelope decorated extracellular vesicles, serve as vehicles for intercellular transmission of protein aggregates, exacerbating the spread of toxic protein misfolding. Importantly, our findings suggest that targeting ERVs with antivirals could offer a new therapeutic strategy to slow down the protein aggregate spreading.

This study uncovers a novel mechanism how ERVs, derepressed in neurodegenerative diseases, could contribute to disease progression. It underscores the need to explore antiviral treatments as a mean to combat the harmful effects of protein aggregate spreading, potentially opening new avenues for disease intervention in Alzheimer’s and related disorders. Our work sheds light on the intricate role that ancient viral elements may play in accelerating protein misfolding, and how controlling these processes could be a key to future treatments.

Title of the publication

„MRI or ¹⁸F-FDG PET for Brain Age Gap Estimation: Links to Cognition, Pathology, and Alzheimer Disease Progression“
in: THE JOURNAL OF NUCLEAR MEDICINE, Vol. 65, No. 1 January 2024

Short summary of the paper

Brain aging is characterized by the accumulation of deleterious biological changes, making it highly susceptible to inter-individual differences. Alzheimer’s disease (AD) patients display a more pronounced decline in brain integrity compared to healthy elderly individuals, suggestive of an acceleration of the brain aging process. Therefore, the difference between brain age and chronological (passport) age—referred to as the brain age gap (BAG)—may provide valuable insights into brain health, and different types of the BAG (e.g., structural or functional) could potentially reflect distinct aspects of AD risk. In this study, brain age was estimated by training machine learning algorithms to estimate chronological age from ¹⁸F-FDG PET (metabolic) or T1-weighted MRI (structural) scans, aiming to identify which AD processes are conveyed by metabolic or structural BAGs. The results indicated that metabolic BAG represented a sensitive marker of early cognitive changes even before measurable cognitive impairment occurs, i.e., already in individuals with only subjective cognitive decline. Structural BAG, by contrast, reliably reflected beta-amyloid levels—one of the hallmark pathologies of AD—as well as objective cognitive impairment; and it predicted imminent progression to dementia. Consequently, structural BAG, in particular, emerges as a promising marker for tracking AD progression and could be valuable for assessing the therapeutic effects of emerging disease-modifying treatments.

Title of the publication

in: Science Translation Magazine Vol. 16, June 05, 2024

Short summary of the paper

In our recent study, we developed a new approach to treat frontotemporal dementia (FTD), a
brain disorder that causes memory loss and changes in behavior. One of the main causes of
FTD is a lack of a protein called progranulin, which helps to protect brain cells. Without enough
progranulin, harmful substances build up in the brain, leading to inflammation and cell death.
To address this, we used a specially designed virus to deliver progranulin to the body. What’s
unique about our method is that it can cross the blood-brain barrier—the natural defense that
prevents most treatments from reaching the brain. Once in the body, the virus makes liver cells
produce progranulin, which travels to the brain and restores its levels, resulting in the clearing
of the harmful substances causing the disease.
We tested this treatment in vivo, and the results were promising: brain inflammation decreased,
and the harmful protein buildup was reduced. We also tested the therapy in human brain cells
grown from stem cells mimicking FTD. These experiments showed similar positive effects,
making the treatment approach even more relevant for future use in humans.
In short, this study offers hope for a new way to treat FTD and potentially other brain diseases.
Our approach could make it easier to deliver treatments to the brain without invasive
procedures.

Title of the publication

„What influences life expectancy in people with dementia? Social support as an emerging protective factor“
in: Age and Ageing 53, afae044 (online first). doi: 10.1093/ageing/afae044

Short summary of the paper

It was long believed that the life expectancy of people with dementia primarily depended on the severity of the disease and accompanying conditions. The COVID-19 pandemic has shed light on how important social contact and support are for people with dementia – and how these factors can positively influence the progression of dementia symptoms, or negatively impact it when absent. In this study, we used data from 500 individuals with dementia who were regularly visited at home over a period of up to eight years and investigated how social support affects life expectancy. For the first time, we demonstrate that social support influences the life expectancy of people with dementia – beyond clinical factors. In our study, individuals who reported receiving more social support had a life expectancy that was one year longer. Particularly important was not practical support, but rather emotional support – such as whether someone offers comfort, listens, and accepts the person with dementia as they are. In addition to social support, younger age, female sex, and lower dementia severity (higher cognitive and daily functioning) were associated with a higher life expectancy. Our study makes an important contribution to improving the care of people with dementia in the future: it shows that not only physical and medical needs, but also psychosocial needs must be given greater attention.

Title of the publication

„Data-driven brain atrophy staging in spinocerebellar ataxia type 3″
in: medRxiv. https://doi.org/10.1101/2024.05.29.24307992

Short summary of the paper

Alzheimer’s disease is highly heterogeneous with previous studies demonstrating significant relationships of its clinical and biological variability. However, it remains unclear whether this heterogeneity can be effectively captured in a memory clinic setting using routinely collected patient data to enable more accurate diagnoses and prognoses.

Using structural MRI from a total of 1592 older adults enrolled in two large-scale memory clinic-based cohorts, Baumeister and colleagues identified two distinct patterns of brain atrophy. Based on these findings, they propose a model capable of classifying individuals by their atrophy subtype—either “limbic-predominant” or “hippocampal-sparing”—and atrophy stage, which is represented as a numeric value ranging from 0 to 10, from a single brain scan.

These classifications are shown to relate to patients’ clinical presentation at the time of the scan. For instance, the limbic-predominant subtype was associated with cognitive impairment primarily affecting memory, while the hippocampal-sparing subtype was linked to more generalized cognitive impairments, including deficits in attention and processing speed. Atrophy classifications were also predictive of patients’ clinical development over a follow-up period of more than four years. Here, especially the limbic-predominant atrophy subtype and higher atrophy stages were strong predictors of declining cognitive functions. Importantly, these predictions could also be made for older adults without manifest cognitive impairment, a key point given the importance of early intervention in light of recent pharmaceutical advances.

Given these results, the proposed model holds significant promise for enhancing the usefulness of structural MRI in a variety of contexts, from routine clinical practice to complex drug trials.

Title of the publication

„Medin co-aggregtes with vascular amyloid-ß in Alzheimer’s disease“
in: Nature, Dezember 2022

„Impact of low-value medications on quality of life, hospitalization and costs – A longitudinal analysis of patients living with dementia“
in: Alzheimer’s & Dementia (2023;1-12)

Zur Gewinnerurkunde

„Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18kDa translocator protein (TSPO)“
in: NATURE NEUROSCIENCE, March 2022, 317-329

Zur Gewinnerurkunde

„Feasibility of a standard cognitive assessment in European academic memory clinics“
in: Alzheimer’s & Dementia (2022; 1-11)

Zur Gewinnerurkunde

„Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregaion of TDP-43“
in: NATURE COMMUNICATIONS (2022); 13

Zur Gewinnerurkunde

„Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases“
in: Science Translational Medicine 13, eabe5640, 13 October 2021

Zur Gewinnerurkunde

„Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions“
in: Nature Communications, (2021)12:5739, October 19, 2021

Title of the publication

„Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes“
in: CellPress 2021, Cell 184, 5089–5106, September 30, 2021

Title of the publication

in: PNAS, September 22, 2020, vol. 117, no. 38, 23925-23931

Title of the publication

„RhoA drives actin compaction to restrict axon regeneration and astrocyte reactivity after CNS injury“
in: CellPress, 3438 Neuron 109, 3436–3455, November 3, 2021

Title of the publication

„Loss of TREM2 function increases amyloidseeding but reduces plaque-associated ApoE“
in: Nat Neurosci 22, 191–204, January 7, 2019

Short summary of the paper

Alois Alzheimer identified three key hallmarks of the disease: the presence of amyloid plaques and tau tangles, as well as increased microglia – immune cells responsible for destruction of invading pathogens in the brain. The microglial gene TREM2 was identified to play a crucial role in sustaining the microglial response in disease conditions. Using an amyloid plaque-depositing in vivo model of Alzheimer’s disease (AD), I found that the loss of TREM2 function increased early plaque accumulation by preventing microglial clearance of plaques. APOE, the strongest genetic risk factor for AD, plays an essential role in promoting plaque formation, and its expression is mainly reported in astrocytes—another key regulator of inflammation. My studies showed that not only was APOE induced in microglia around plaques, but was also strongly reduced upon TREM2 deficiency. This suggests therapeutic strategies must consider TREM2-APOE interaction as it may protectively modulate plaque clearance, but in parallel exacerbate amyloid pathology.