Mouse Models Of Neurodegenerative Diseases Research Articles

HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signatures in vitro.

Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes 1 . Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans 2-6 ; however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate 7,8 . Here, we present a pharmacological approach to mimic human DAM in vitro by exposing different human microglia models to selected histone deacetylase (HDAC) inhibitors. We also provide an initial functional characterization of our model system, showing a specific increase of amyloid beta phagocytosis along with a reduction of MCP-1 secretion. Additionally, we report an increase in MITF expression, a transcription factor previously described to drive expression towards the DAM phenotype. We further identify CADM1 , LIPA and SCIN as DAM- marker genes shared across various proposed DAM signatures and in our model systems. Overall, our strategy for targeted microglial polarization bears great potential to further explore human DAM function and biology.

The reverse transcriptase inhibitor 3TC modulates hippocampal transcriptome signatures of inflammation in tauopathy model mice

Reducing neuroinflammation, a key contributor to brain aging and neurodegenerative diseases, is a promising strategy for improving cognitive function in these settings. The FDA-approved nucleoside reverse transcriptase inhibitor 3TC (Lamivudine) has been reported to improve cognitive function in old wild-type mice and multiple mouse models of neurodegenerative disease, but its effects on the brain have not been comprehensively investigated. In the current study, we used transcriptomics to broadly characterize the effects of long-term supplementation with a human-equivalent therapeutic dose of 3TC on the hippocampal transcriptome in male and female rTg4510 mice (a commonly studied model of tauopathy-associated neurodegeneration). We found that tauopathy increased hippocampal transcriptomic signatures of neuroinflammation/immune activation, but 3TC treatment reversed some of these effects. We also found that 3TC mitigated tauopathy-associated activation of key transcription factors that contribute to neuroinflammation and immune activation, and these changes were related to improved recognition memory performance. Collectively, our findings suggest that 3TC exerts protective effects against tauopathy in the hippocampus by modulating inflammation and immune activation, and they may provide helpful insight for ongoing clinical efforts to determine if 3TC and/or related therapeutics hold promise for treating neurodegeneration.

Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer's disease.

Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor erythroid 2-related factor 2 (Nrf2) attenuates neuroinflammation in the mouse models of neurodegenerative diseases, however, the detailed mechanism remains unclear. The effects of dimethyl fumarate (DMF), a clinically used drug to activate the Nrf2 pathway, on neuroinflammation were analyzed in primary astrocytes and AppNL-G-F (App-KI) mice. The cognitive function and behavior of DMF-administrated App-KI mice were evaluated. For the gene expression analysis, microglia and astrocytes were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, followed by quantitative PCR. DMF treatment activated some Nrf2 target genes and inhibited the expression of proinflammatory markers in primary astrocytes. Moreover, chronic oral administration of DMF attenuated neuroinflammation, particularly in astrocytes, and reversed cognitive dysfunction presumably by activating the Nrf2-dependent pathway in App-KI mice. Furthermore, DMF administration inhibited the expression of STAT3/C3 and C3 receptor in astrocytes and microglia isolated from App-KI mice, respectively, suggesting that the astrocyte-microglia crosstalk is involved in neuroinflammation in mice with AD. The activation of astrocytic Nrf2 signaling confers neuroprotection in mice with AD by controlling neuroinflammation, particularly by regulating astrocytic C3-STAT3 signaling. Furthermore, our study has implications for the repositioning of DMF as a drug for AD treatment.

Validity and value of metabolic connectivity in mouse models of β-amyloid and tauopathy

Among functional imaging methods, metabolic connectivity (MC) is increasingly used for investigation of regional network changes to examine the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) or movement disorders. Hitherto, MC was mostly used in clinical studies, but only a few studies demonstrated the usefulness of MC in the rodent brain. The goal of the current work was to analyze and validate metabolic regional network alterations in three different mouse models of neurodegenerative diseases (β-amyloid and tau) by use of 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) imaging. We compared the results of FDG-µPET MC with conventional VOI-based analysis and behavioral assessment in the Morris water maze (MWM). The impact of awake versus anesthesia conditions on MC read-outs was studied and the robustness of MC data deriving from different scanners was tested. MC proved to be an accurate and robust indicator of functional connectivity loss when sample sizes ≥12 were considered. MC readouts were robust across scanners and in awake/ anesthesia conditions. MC loss was observed throughout all brain regions in tauopathy mice, whereas β-amyloid indicated MC loss mainly in spatial learning areas and subcortical networks. This study established a methodological basis for the utilization of MC in different β-amyloid and tau mouse models. MC has the potential to serve as a read-out of pathological changes within neuronal networks in these models.

Assessment of apathy‐like behaviour in transgenic mouse models of neurodegenerative diseases

AbstractBackgroundApathy is the most common behavioural and psychological symptom in neurodegenerative diseases like Alzheimer’s disease (AD), frontotemporal dementia (FTD) or Parkinson’s disease (PD). Apathy typically includes a loss of motivation, initiative and interest, listlessness and indifference, flattening of emotions, absence of drive and passion. Scientists have defined this as a reduction/lack in goal direct behaviour. There are currently no specific treatment options for apathy. In experimental models, selective symptoms of apathy‐like behaviour are measured in goal directed or nesting behavioural tasks, which report on their motivation to perform daily activities. A richer understanding of apathy, however, may be achieved through the development of a battery of tests including goal directed, nesting, anhedonia, activity monitoring, and social interaction. These have been applied here to several animal models of neurodegeneration.MethodMale and female transgenic mice (aged 6 – 8 months) including tau over‐expressors L1 for AD and L66 for FTD (Melis et al. 2015); PLB4 BACE1 mouse model for AD (Plucinska et al. 2014); L62 alpha‐synuclein mouse model of PD (Frahm et al. 2018) and relevant wild type (WT) controls were utilised in this study. Animals were tested in a series of behavioural tests including the nest building task, sucrose preference test, buried cookie test, social interaction, and home cage activity. Performance was recorded and analysed by behavioural tracking software as indicators of apathy‐like behaviour.ResultTwo models showed reproducible results compared with previous studies. Intriguingly, L66 FTD mice presented with deficits in sucrose preference and nest‐building, but not a lowering of general activity. Although this was not found for the sister strain, L1 mice which has AD‐like pathology. Very much unexpected is the observation that neither the amyloid nor the synuclein‐based models showed any significant behavioural anomalies. Further detailed investigations are ongoing.ConclusionInitial observations have confirmed that the transgenic models for neurodegenerative diseases show different levels of apathy‐like behaviour. It appears that the phenotype in L66 is a tau‐related anomaly specific to the tau species expressed, i.e. the mutation at P301S. The lack of deficits in all other models warrants in‐depth confirmation and analysis.

IBC‐Ab002 Fc modifications for fast clearance are associated with advantageous safety profile

AbstractBackgroundImmune checkpoint inhibitors (ICI) have been suggested as a unique therapy for treating neurodegenerative diseases. IBC‐Ab002 is a novel fully human anti‐PD‐L1 monoclonal antibody developed by ImmunoBrain Checkpoint (IBC) for the treatment of Alzheimer’s disease (AD).In cancer patients, ICI treatments are often associated with immune‐related adverse events (irAEs), which are side effects that manifest as either temporary or permanent autoimmune conditions caused by drug administration. One example of such an event is T cell‐mediated pancreatic tissue damage leading to autoimmune diabetes. The management of irAE often involves treatment discontinuation until symptoms relief, which has unwanted impact on the effectiveness of therapies that depend on continuous drug exposure.Unlike common ICI used in oncology, PD‐L1 blockade mechanism of action in mouse models of neurodegenerative diseases was shown to be dependent on transient immune system stimulation. Accordingly, IBC‐Ab002 antibody was designed with modifications on its Fc backbone that shorten its circulation half‐life, to meet the pharmacokinetic and pharmacodynamic characteristics needed for treating AD.MethodSurrogate antibodies that block mouse PD‐L1 and share the same hIgG1 Fc‐modifications as IBC‐Ab002 were generated and tested for their propensity to accelerate the onset of autoimmune diabetes in NOD transgenic mice, which spontaneously develop type 1 diabetes. Mice were monitored for their blood‐glucose levels, weight, and survival – for both the acute and long‐term duration following antibody administration.ResultWe found that administration of a therapeutically effective dose of IBC‐Ab002’s surrogate antibody led to fewer cases of premature diabetes onset in NOD mice, when compared with an antibody variant that contains no Fc‐modifications. Furthermore, no excessive weight loss, change in the time‐course of spontaneous diabetes onset or early mortality, were found following IBC‐Ab002’s surrogate treatment, compared with isotype‐control treated mice, in a 200‐days follow‐up assessment.ConclusionWe demonstrate that the clearance rate of the antibody inversely‐relates to the probability of developing an adverse immune response, and that no delayed long‐term irAEs are expected once full clearance of the antibody was achieved. Overall, these findings suggest that shortening the half‐life of anti‐PD‐L1 antibodies in treatments that do not necessitate continuous exposure can considerably increase the safety profile.

Aldh1a1 and additional markers of dopamine cell heterogeneity in substantia nigra and ventral tegmental area identified as preserved in two transgenic α-synuclein mouse models of neurodegenerative disease

Aim: Parkinson’s disease (PD) is characterized by degeneration of midbrain dopamine neurons and synucleinopathy [aggregated alpha-synuclein protein (αSyn)]. The correlation between αSyn pathology and dopamine neuron degeneration remains to be fully established. Mouse models of PD are commonly used to increase knowledge of disease mechanisms. Lately, midbrain dopamine neurons have gained attention as more heterogeneous than previously recognized. With the aim to determine how the midbrain dopamine system in mice is affected in the presence of αSyn pathology, this brain system was studied in two transgenic mouse models of synucleinopathy. Methods: Brain sections from two previously described transgenic mouse lines verified for αSyn pathology through expression of the human αSyn gene (SNCA) under control of the Thy-1 promoter [Thy1-h[A30P]αSyn and Thy1-h[wt]αSyn (L61)], were analyzed using fluorescent in situ hybridization (FISH) and compared with matching sections from wild-type control mice. Probes directed towards mouse and human αSyn mRNA, and a battery of probes towards mRNAs representative of dopamine cell identity and heterogeneity, were implemented. Results: First, validation of αSyn-encoding mRNA was performed. Ample ectopic αSyn mRNA was observed throughout the brain of mice of each transgenic line. Next, midbrain dopamine neurons located in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were analyzed using a battery of general and subpopulation-specific dopamine cell markers. This included tyrosine hydroxylase (Th), vesicular monoamine transporter 2 (Vmat2), dopamine transporter (Dat), aldehyde dehydrogenase 1 family member A1 (Aldh1a1), G-protein-activated inward-rectifying potassium channel type 2 (Girk2), calbindin 1 (Calb1), Calb2, gastrin-releasing peptide (Grp), and vesicular glutamate transporter 2 (Vglut2) mRNAs. No difference between transgenic and control mice was observed for any analyzed marker in either the Thy1-h[A30P]αSyn or Thy1-h[wt]αSyn transgenic mouse line. Conclusions: This study demonstrates remarkable robustness of midbrain dopamine cell integrity in the presence of brain-wide ectopic human αSyn in two transgenic mouse models of neurodegenerative disease, motivating further study into mechanisms correlating synucleinopathy with dopamine neuron degeneration in rodent models relevant to PD.

Hawaiian native herb Mamaki prevents dementia by ameliorating neuropathology and repairing neurons in four different mouse models of neurodegenerative diseases.

Neurodegenerative diseases including Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies are age-related disorders and the main cause of dementia. They are characterized by the cerebral accumulation of Aβ, tau, α-synuclein, and TDP-43. Because the accumulation begins decades before disease onset, treatment should be started in the preclinical stage. Such intervention would be long-lasting, and therefore, prophylactic agents should be safe, non-invasively taken by the patients, and inexpensive. In addition, the agents should be broadly effective against etiologic proteins and capable of repairing neurons damaged by toxic oligomers. These requirements are difficult to meet with single-ingredient pharmaceuticals but may be feasible by taking proper diets composed of multiple ingredients. As a source of such diets, we focused on the Hawaiian native herb Mamaki. From its dried leaves and fruits, we made three preparations: hot water extract of the leaves, non-extracted simple crush powder of the leaves, and simple crush powder of the fruits, and examined their effects on the cognitive function and neuropathologies in four different mouse models of neurodegenerative dementia. Hot water extract of the leaves attenuated neuropathologies, restored synaptophysin levels, suppressed microglial activation, and improved memory when orally administered for 1month. Simply crushed leaf powder showed a higher efficacy, but simply crushed fruit powder displayed the strongest effects. Moreover, the fruit powder significantly enhanced the levels of brain-derived neurotrophic factor expression and neurogenesis, indicating its ability to repair neurons. These results suggest that crushed Mamaki leaves and fruits are promising sources of dementia-preventive diets.

The gene expression patterns as surrogate indices of pH in the brain.

Hydrogen ion (H+) is one of the most potent intrinsic neuromodulators in the brain in terms of concentration. Changes in H+ concentration, expressed as pH, are thought to be associated with various biological processes, such as gene expression, in the brain. Accumulating evidence suggests that decreased brain pH is a common feature of several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and Alzheimer's disease. However, it remains unclear whether gene expression patterns can be used as surrogates for pH changes in the brain. In this study, we performed meta-analyses using publicly available gene expression datasets to profile the expression patterns of pH-associated genes, whose expression levels were correlated with brain pH, in human patients and mouse models of major central nervous system (CNS) diseases, as well as in mouse cell-type datasets. Comprehensive analysis of 281 human datasets from 11 CNS disorders revealed that gene expression associated with decreased pH was over-represented in disorders including schizophrenia, bipolar disorder, autism spectrum disorders, Alzheimer's disease, Huntington's disease, Parkinson's disease, and brain tumors. Expression patterns of pH-associated genes in mouse models of neurodegenerative disease showed a common time course trend toward lower pH over time. Furthermore, cell type analysis identified astrocytes as the cell type with the most acidity-related gene expression, consistent with previous experimental measurements showing a lower intracellular pH in astrocytes than in neurons. These results suggest that the expression pattern of pH-associated genes may be a surrogate for the state- and trait-related changes in pH in brain cells. Altered expression of pH-associated genes may serve as a novel molecular mechanism for a more complete understanding of the transdiagnostic pathophysiology of neuropsychiatric and neurodegenerative disorders.

The KEAP1-NRF2 System and Neurodegenerative Diseases.

Significance: Central nervous system (CNS) diseases are disorders of the brain and/or spinal cord and include neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor belonging to the cap-n-collar family that harbors a unique basic leucine zipper motif and plays as a master regulator of homeostatic responses. Recent Advances: Kelch-like ECH-associated protein 1 (KEAP1) is an adaptor of the Cullin3 (CUL3)-based ubiquitin E3 ligase that enhances the ubiquitylation of NRF2, which promotes the degradation of NRF2 to suppress its transcriptional activity in the absence of stress. Cysteine residues of KEAP1 are modified under stress conditions, and NRF2 degradation is attenuated, allowing it to accumulate and induce the expression of target genes. This regulatory system is referred to as the KEAP1-NRF2 system and plays a central role in protecting cells against various stresses. NRF2 also negatively regulates the expression of inflammatory cytokine and chemokine genes and suppresses pathological inflammation. As oxidative stress, inflammation, and proteostasis are known to contribute to neurodegenerative diseases, the KEAP1-NRF2 system is an attractive target for the treatment of these diseases. Critical Issues: In mouse models of neurodegenerative diseases, Nrf2 depletion exacerbates symptoms and enhances oxidative damage and inflammation in the CNS. In contrast, chemical or genetic NRF2 activation improves these symptoms. Indeed, the NRF2-activating chemical dimethyl fumarate is now widely used for the clinical treatment of MS. Future Directions: The KEAP1-NRF2 system is a promising therapeutic target for neurodegenerative diseases.

The KEAP1-NRF2 system and neurodegenerative diseases.

Significance: Central nervous system (CNS) diseases are disorders of the brain and/or spinal cord and include neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). NF-E2-related factor 2 (NRF2) is a transcription factor belonging to the cap-n-collar (CNC) family that harbors a unique basic leucine zipper motif and plays as a master regulator of homeostatic responses. Recent Advances: Kelch-like ECH-associated protein 1 (KEAP1) is an adaptor of the Cullin3 (CUL3)-based ubiquitin E3 ligase that enhances the ubiquitylation of NRF2, which promotes the degradation of NRF2 to suppress its transcriptional activity in the absence of stress. Cysteine residues of KEAP1 are modified under stress conditions, and NRF2 degradation is attenuated, allowing it to accumulate and induce the expression of target genes. This regulatory system is referred to as the KEAP1-NRF2 system and plays a central role in protecting cells against various stresses. NRF2 also negatively regulates the expression of inflammatory cytokine and chemokine genes and suppresses pathological inflammation. As oxidative stress, inflammation, and proteostasis are known to contribute to neurodegenerative diseases, the KEAP1-NRF2 system is an attractive target for the treatment of these diseases. Critical Issues: In mouse models of neurodegenerative diseases, Nrf2 depletion exacerbates symptoms and enhances oxidative damage and inflammation in the CNS. In contrast, chemical or genetic NRF2 activation improves these symptoms. Indeed, the NRF2-activating chemical dimethyl fumarate (DMF) is now widely used for the clinical treatment of MS. Future Directions: The KEAP1-NRF2 system is a promising therapeutic target for neurodegenerative diseases.

Relevance of the pre‐clinical models in TBI

AbstractIn the absence of any effective translation from preclinical models to clinical application, what has been achieved by laboratory models of TBI? Analysis and assimilation of results from preclinical TBI studies is confounded by the heterogeneity of the models and the TBI paradigms employed. Variance in animal, injury location, severity, number, frequency, age of animal at injury and age of animal at analyses, not to mention the research focus of the investigators themselves, all contribute to the difficulties in data integration and interpretation. Nonetheless, preclinical TBI research has identified areas of focus and enabled creation of timelines of TBI pathobiology. Ultimately, validation of any potential therapeutic targets will require exploitation of the heterogeneity of preclinical models in order to facilitate clinical translation, given the heterogeneity of the patient population.In the course of modeling TBI paradigms in (primarily) mouse models, the failure of recapitulation of TBI‐dependent neurodegenerative pathology representing AD, PD, ALS etc. has prompted the use of mouse models of neurodegenerative disease, expressing genetic risk factors or humanized for proteins implicated in human neurodegenerative diseases, in efforts to understand how TBI can exacerbate or even precipitate the neurodegenerative pathobiology. These investigations have generated many interesting observations, not always easily consolidated into any clear pathogenic mechanism, but some overarching themes have emerged. Some of the published TBI approaches, and findings, will be reviewed, and knowledge gaps and future directions will be discussed.

Immuno(T)herapy for age-related diseases.

During the last decade, the stimulation of T-cell function by the blockage of immunosuppressive checkpoints has experienced an outstanding impact in the treatment of cancer. Development of the chimeric antigen receptor T-cell technology has also emerged as a powerful alternative for patients suffering from oncological processes, especially those affected by hematological neoplasms. Recent evidence suggest that the use of immunotherapy could be extended to non-oncological diseases and could be especially relevant for age-associated disorders, opening exciting therapeutic options for a wide range of diseases of the elderly. Here we comment on the emergence of T-cell-based immunotherapies as feasible approaches that could revolutionize the future of GeroScience.

Development of microglia-targeting adeno-associated viral vectors as tools to study microglial behavior in vivo

Here we describe the microglia-targeting adeno-associated viral (AAV) vectors containing a 1.7-kb putative promoter region of microglia/macrophage-specific ionized calcium-binding adaptor molecule 1 (Iba1), along with repeated miRNA target sites for microRNA (miR)-9 and miR-129-2-3p. The 1.7-kb genomic sequence upstream of the start codon in exon 1 of the Iba1 (Aif1) gene, functions as microglia preferential promoter in the striatum and cerebellum. Furthermore, ectopic transgene expression in non-microglial cells is markedly suppressed upon adding two sets of 4-repeated miRNA target sites for miR-9 and miR-129-2-3p, which are expressed exclusively in non-microglial cells and sponged AAV-derived mRNAs. Our vectors transduced ramified microglia in healthy tissues and reactive microglia in lipopolysaccharide-treated mice and a mouse model of neurodegenerative disease. Moreover, live fluorescent imaging allowed the monitoring of microglial motility and intracellular Ca2+ mobilization. Thus, microglia-targeting AAV vectors are valuable for studying microglial pathophysiology and therapies, particularly in the striatum and cerebellum.

Abnormal whisker movements in the 3xTg-AD mouse model of Alzheimer's disease.

Alzheimer's disease is the most frequent form of dementia in elderly people. The triple transgenic (3xTg-AD) mouse model of Alzheimer's Disease is important in biomedical research as these mice develop both neuropathological and behavioural phenotypes. However, their behavioural phenotype is variable, with findings depending on the specific task, as well as the age and sex of the mice. Whisker movements show motor, sensory and cognitive deficits in mouse models of neurodegenerative disease. Therefore, we examined whisker movements in 3, 12.5 and 17-month-old female 3xTg-AD mice and their B6129S/F2 wildtype controls. Mice were filmed using a high-speed video camera (500 fps) in an open arena during a novel object exploration task. Genotype and age differences were found in mice exploring the arena prior to object contact. Prior to whisker contact, the 3-month-old 3xTg-AD mice had smaller whisker angles compared with the wildtype controls, suggesting an early motor phenotype in these mice. Pre-contact mean angular position at 3months and whisking amplitude at 17 months of age differed between the 3xTg-AD and wildtype mice. During object contact 3xTg-AD mice did not reduce whisker spread as frequently as the wildtype mice at 12.5 and 17 months, which may suggest sensory or attentional deficits. We show that whisker movements are a powerful behavioural measurement tool for capturing behavioural deficits in mouse models that show complex phenotypes, such as the 3xTg-AD mouse model.

BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis.

In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.

Genetic ablation of Gpnmb does not alter synuclein-related pathology

The gene GPNMB is known to play roles in phagocytosis and tissue repair, and is upregulated in microglia in many mouse models of neurodegenerative disease as well as in human patients. Nearby genomic variants are associated with both elevated Parkinson's disease (PD) risk and higher expression of this gene, suggesting that inhibiting GPNMB activity might be protective in Parkinson's disease. We tested this hypothesis in three different mouse models of neurological diseases: a remyelination model and two models of alpha-synuclein pathology. We found that Gpnmb deletion had no effect on histological, cellular, behavioral, neurochemical or gene expression phenotypes in any of these models. These data suggest that Gpnmb does not play a major role in the development of pathology or functional defects in these models and that further work is necessary to study its role in the development or progression of Parkinson's disease.

In vivo imaging of synaptic density with [11C]UCB-J PET in two mouse models of neurodegenerative disease

The positron emission tomography (PET) radioligand [11C]UCB-J binds to synaptic vesicle protein 2A (SV2A) and is used to investigate synaptic density in the living brain. Clinical studies have indicated reduced [11C]UCB-J binding in Alzheimer's disease (AD) and Parkinson's disease (PD) brains compared to healthy controls. Still, it is unknown whether [11C]UCB-J PET can visualise synaptic loss in mouse models of these disorders. Such models are essential for understanding disease pathology and for evaluating the effects of novel disease-modifying drug candidates. In the present study, synaptic density in transgenic models of AD (ArcSwe) and PD (L61) was studied using [11C]UCB-J PET. Data were acquired during 60 min after injection, and time-activity curves (TACs) in different brain regions and the left ventricle of the heart were generated based on the dynamic PET images. The [11C]UCB-J brain concentrations were expressed as standardised uptake value (SUV) over time. The area under the SUV curve (AUC), the ratio of AUC in the brain to that in the heart (AUCbrain/blood), and the volume of distribution (VT) obtained by kinetic modelling using the heart TAC as input were compared between transgenic and age-matched wild type (WT) mice. The L61 mice displayed 11–13% lower AUCbrain/blood ratio and brain VT generated by kinetic modeling compared to the control WT mice. In general, also transgenic ArcSwe mice tended to show lower [11C]UCB-J brain exposure than age-matched WT controls, but variation within the different animal groups was high. Older WT mice (18–20 months) showed lower [11C]UCB-J brain exposure than younger WT mice (8–9 months). Together, these data imply that [11C]UCB-J PET reflects synaptic density in mouse models of neurodegeneration and that inter-subject variation is large. In addition, the study suggested that model-independent AUCbrain/blood ratio can be used to evaluate [11C]UCB-J binding as an alternative to full pharmacokinetic modelling.

Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro‐inflammatory senescence‐associated secretory phenotype (SASP), which is a major contributor to aging and age‐related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single‐nuclei and single‐cell RNA‐seq in the hippocampus from young and aged mice. We observed an age‐dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK‐ATTAC mice, in which p16Ink4a‐positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof‐of‐concept for senolytic interventions' being a potential therapeutic avenue for alleviating age‐associated cognitive impairment.

MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease.

Oxidative stress is a major risk factor for Alzheimer's disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.