An immunological puzzle: The adaptive immune system fuels Alzheimer's disease pathology.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a concerning rise in prevalence. It is projected that the number of affected individuals will reach a staggering 150 million by 2050. While recent advancements in monoclonal antibodies targeting Aß have shown some clinical effects, there is an urgent need for improved therapies to effectively address the impeding surge of AD patients worldwide. To achieve this, a deeper understanding of the intricate mechanisms underlying the disease is crucial. In recent years, mounting evidence has underscored the vital role of the innate immune system in AD pathology. However, limited findings persist regarding the involvement of the adaptive immune system. Here, we report on the impact of the adaptive immune system on various aspects of AD by using AppNL-G-F mice crossed into a Rag2-/- background lacking mature adaptive immune cells. In addition, to simulate the continuous exposure to various challenges such as infections that is commonly observed in humans, the innate immune system was activated through the repetitive induction of peripheral inflammation. We observed a remarkably improved performance on complex cognitive tasks when a mature adaptive immune system is absent. Notably, this observation is pathologically associated with lower Aß plaque accumulation, reduced glial activation, and better-preserved neuronal networks in the mice lacking a mature adaptive immune system. Collectively, these findings highlight the detrimental role of the adaptive immune system in AD and underscore the need for effective strategies to modulate it for therapeutic purposes.

Limitations of PLX3397 as a microglial investigational tool: peripheral and off-target effects dictate the response to inflammation.

Microglia, the resident macrophages of the central nervous system (CNS), play a critical role in CNS homeostasis and neuroinflammation. Pexidartinib (PLX3397), a colony-stimulating factor 1 (CSF1) receptor inhibitor, is widely used to deplete microglia, offering flexible options for both long-term depletion and highly versatile depletion-repopulation cycles. However, the potential impact of PLX3397 on peripheral (immune) cells remains controversial. Until now, the microglia-specificity of this type of compounds has not been thoroughly evaluated, particularly in the context of peripherally derived neuroinflammation. Our study addresses this gap by examining the effects of PLX3397 on immune cells in the brain, liver, circulation and bone marrow, both in homeostasis and systemic inflammation models. Intriguingly, we demonstrate that PLX3397 treatment not only influences the levels of tissue-resident macrophages, but also affects circulating and bone marrow immune cells beyond the mononuclear phagocyte system (MPS). These alterations in peripheral immune cells disrupt the response to systemic inflammation, consequently impacting the phenotype irrespective of microglial depletion. Furthermore, we observed that a lower dose of PLX3397, which does not deplete microglia, demonstrates similar (non-)MPS effects, both in the periphery and the brain, but fails to fully replicate the peripheral alterations seen in the higher doses, questioning lower doses as a 'peripheral control' strategy. Overall, our data highlight the need for caution when interpreting studies employing this compound, as it may not be suitable for specific investigation of microglial function in the presence of systemic inflammation.

Structural connectivity and weight loss in children with obesity: a study of the "connectobese".

BACKGROUND: Previous studies suggest that obesity (OB) is associated with disrupted brain network organization; however, it remains unclear whether these differences already exist during childhood. Moreover, it should be investigated whether deviant network organization may be susceptible to treatment. METHODS: Here, we compared the structural connectomes of children with OB with age-matched healthy weight (HW) controls (aged 7-11 years). In addition, we examined the effect of a multidisciplinary treatment program, consisting of diet restriction, cognitive behavioral therapy, and physical activity for children with OB on brain network organization. After stringent quality assessment criteria, 40 (18 OB, 22 HW) data sets of the total sample of 51 participants (25 OB, 26 HW) were included in further analyses. For all participants, anthropometric measurements were administered twice, with a 5-month interval between pre- and post tests. Pre- and post T1- and diffusion-weighted imaging scans were also acquired and analyzed using a graph-theoretical approach and network-based statistics. RESULTS: Global network analyses revealed a significantly increased normalized clustering coefficient and small-worldness in children with OB compared with HW controls. In addition, regional analyses revealed increased betweenness centrality, reduced clustering coefficient, and increased structural network strength in children with OB, mainly in the motor cortex and reward network. Importantly, children with OB lost a considerable amount of their body mass after the treatment; however, no changes were observed in the organization of their brain networks. CONCLUSION: This is the first study showing disrupted structural connectomes of children with OB, especially in the motor and reward network. These results provide new insights into the pathophysiology underlying childhood obesity. The treatment did result in a significant weight loss, which was however not associated with alterations in the brain networks. These findings call for larger samples to examine the impact of short-term and long-term weight loss (treatment) on children's brain network organization.

Weight loss, behavioral change, and structural neuroplasticity in children with obesity through a multidisciplinary treatment program.

This study evaluated the effect of a multidisciplinary treatment program for children with obesity (OB) on motor competence, executive functioning (EF), and brain structure. Nineteen children with OB (7-11 years), who attended a multidisciplinary treatment program consisting of diet restriction, cognitive behavioral therapy, and physical activity, were compared with an age-matched control group of 24 children with a healthy weight (HW), who did not follow any treatment. For both groups, anthropometric measurements and tests of motor competence and EF were administered twice, with 5 months between pretest and posttest. Additionally, children's brain structure was assessed by performing a magnetic resonance imaging (MRI) scan at the pretest and posttest, which included a T1 anatomical scan, diffusion MRI scan, and magnetization transfer imaging scan. Compared to HW controls, children with OB lost a considerable amount of their body mass (p ≤ .001) and significantly improved their balance skills (p ≤ .001), while no transfer effects of the program were observed for EF. Furthermore, the program resulted in a significant increase in total (p ≤ .001) and cerebellar (p ≤ .001) gray matter volume in children with OB, while no change was observed in the HW controls. Finally, only weak to moderate (nonsignificant) correlations could be observed between structural brain alterations, weight-related changes, and behavioral improvements. Altogether, this is the first longitudinal study showing behavioral and structural brain alterations in response to a multidisciplinary weight loss program for children with OB. Our findings support the need for multidimensional intervention (and prevention) measures for children with OB to deal with this multifactorial health problem.

Role of Motor Competence and Executive Functioning in Weight Loss: A Study in Children with Obesity.

OBJECTIVE: This study aimed to compare motor competence and executive functioning (EF) between children with obesity and peers with healthy weight. Additionally, the predictive value of motor competence and EF in weight loss after a 5-month multidisciplinary residential treatment program was examined. METHODS: Thirty-two children with obesity (7-11 years, 14 boys) and 32 age-matched controls (18 boys) performed 8 motor skill tasks and 4 tasks of EF (only at baseline). In the group of children with obesity, anthropometric measurements were performed at baseline and 5 months after the start of their treatment program. Also in control children, there was a time span of 5 months in between anthropometric measurements. RESULTS: Lower levels of motor competence and reduced updating abilities, inhibition control, and planning skills were observed in children with obesity compared with healthy-weight controls. Within the total group, better general motor competence and balance skills were significantly associated with better updating, inhibition control, and planning. Finally, hierarchical regression analyses revealed that ball skills, balance skills, and inhibition/updating at baseline predicted 14% to 17% of the variance in weight loss after a 5-month treatment program in children with obesity. CONCLUSION: These results suggest that motor competence and EF are both relevant factors associated with childhood obesity. Moreover, these factors seem to be significant predictors of weight loss. Future (intervention) studies are needed to understand the impact of the difficulties in motor and EF on obesity-related behaviors as well as on short-term and, especially, long-term weight loss and maintenance.

Reduced motor competence in children with obesity is associated with structural differences in the cerebellar peduncles.

Previous studies have suggested that neurological factors partly explain the reduced motor competence found in many children with obesity. Accordingly, the aim of this study was to compare motor competence and white matter organization of important pathways for motor control (cerebellar peduncles) in children with and without obesity. Nineteen children with obesity and 25 children with a healthy weight, aged 7-11 years old, were included. Anthropometric measurements were taken and the level of motor competence was assessed using the Movement Assessment Battery for Children (2nd Edition). Children's brain was scanned using diffusion weighted imaging preceded by a standard anatomical scan. Fractional anisotropy and mean diffusivity were extracted from the cerebellar peduncles. Obese children's level of motor competence was significantly lower than that in healthy weight peers (p < 0.05). Additionally, significant group differences (p < 0.05) were found for values of fractional anisotropy, but not for mean diffusivity. Further analyses revealed that lower values of fractional anisotropy in the inferior (p = 0.040) and superior (p = 0.007) cerebellar peduncles were present in children with obesity compared to children with a healthy weight. After controlling for multiple comparisons (p < 0.0167), only significant differences in the superior cerebellar peduncle remained significant. Our results showed that childhood obesity is accompanied by reduced motor competence and alterations in white matter organization. This suggests that the motor difficulties of children with obesity are not solely due to carrying excess weight, which may have implications for prevention and intervention programs.