Benefits of global mutant huntingtin lowering diminish over time in a Huntington's disease mouse model.

We have developed an inducible Huntington's disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (~50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow-up revealed that the benefits, in all mHtt-lowering groups, attenuated by 12 months of age. While early mHtt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12 months of age, and late mHtt lowering did not ameliorate striatal transcriptional dysregulation at 12 months of age. Only early mHtt lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule HTT-lowering therapeutics progress to the clinic, our findings suggest that moderate mHtt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of mHTT lowering required to sustain long-term benefits in humans.

ß-secretase inhibition prevents structural spine plasticity deficits in App NL-G-F mice.

All clinical BACE1-inhibitor trials for the treatment of Alzheimer's Disease (AD) have failed due to insufficient efficacy or side effects like worsening of cognitive symptoms. However, the scientific evidence to date suggests that BACE1-inhibition could be an effective preventative measure if applied prior to the accumulation of amyloid-beta (Aß)-peptide and resultant impairment of synaptic function. Preclinical studies have associated BACE1-inhibition-induced cognitive deficits with decreased dendritic spine density. Therefore, we investigated dose-dependent effects of BACE1-inhibition on hippocampal dendritic spine dynamics in an APP knock-in mouse line for the first time. We conducted in vivo two-photon microscopy in the stratum oriens layer of hippocampal CA1 neurons in 3.5-month-old App NL-G-F GFP-M mice over 6 weeks to monitor the effect of potential preventive treatment with a high and low dose of the BACE1-inhibitor NB-360 on dendritic spine dynamics. Structural spine plasticity was severely impaired in untreated App NL-G-F GFP-M mice, although spines were not yet showing signs of degeneration. Prolonged high-dose BACE1-inhibition significantly enhanced spine formation, improving spine dynamics in the AD mouse model. We conclude that in an early AD stage characterized by low Aß-accumulation and no irreversible spine loss, BACE1-inhibition could hold the progressive synapse loss and cognitive decline by improving structural spine dynamics.

Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition.

We undertook longitudinal ß-amyloid positron emission tomography (Aß-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in Aß model mice. We thus tested the hypothesis this treatment would rescue from increases of the Aß-PET signal while promoting spatial learning and preservation of synaptic density. Here, we investigated longitudinally for 5 months PS2APP mice (N = 23; baseline age: 8 months) and App NL-G-F mice (N = 37; baseline age: 5 months) using Aß-PET. Groups of mice were treated with pioglitazone or vehicle during the follow-up interval. We tested spatial memory performance and confirmed terminal PET findings by immunohistochemical and biochemistry analyses. Surprisingly, Aß-PET and immunohistochemistry revealed a shift toward higher fibrillary composition of Aß-plaques during upon chronic pioglitazone treatment. Nonetheless, synaptic density and spatial learning were improved in transgenic mice with pioglitazone treatment, in association with the increased plaque fibrillarity. These translational data suggest that a shift toward higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the Aß-PET signal upon immunomodulatory treatments targeting Aß aggregation can thus be protective.

Development of a ligand for in vivo imaging of mutant huntingtin in Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11C ([11C]CHDI-180R) allowed noninvasive monitoring of mHTT pathology in the brain and could track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression in a rodent model. We further showed that in these animals, therapeutic agents that lowered mHTT in the striatum had a functional restorative effect that could be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation.

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Methods: Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of the peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP, AppNL-G-F ). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and ß-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Results: Pioglitazone-treated female PS2APP and AppNL-G-F mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male AppNL-G-F mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R = -0.874, p < 0.0001) but not in vehicle controls (R = -0.356, p = 0.081). Reduced TSPO-PET signal upon pharmacological treatment was associated with better spatial learning despite higher fibrillar ß-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R = 0.952, p < 0.0001). Conclusion: TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Sex and pre-therapeutic assessment of baseline microglial activation predict individual immunomodulation effects and may serve for responder stratification.

Microbiota-derived short chain fatty acids modulate microglia and promote Aß plaque deposition.

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer's disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aß deposition. Germ-free (GF) AD mice exhibit a substantially reduced Aß plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Aß plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Aß plaques upon SCFA supplementation, microglia contained less intracellular Aß. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Aß deposition likely via modulation of the microglial phenotype.

The transcriptional coactivator and histone acetyltransferase CBP regulates neural precursor cell development and migration.

CREB (cyclic AMP response element binding protein) binding protein (CBP, CREBBP) is a ubiquitously expressed transcription coactivator with intrinsic histone acetyltransferase (KAT) activity. Germline mutations within the CBP gene are known to cause Rubinstein-Taybi syndrome (RSTS), a developmental disorder characterized by intellectual disability, specific facial features and physical anomalies. Here, we investigate mechanisms of CBP function during brain development in order to elucidate morphological and functional mechanisms underlying the development of RSTS. Due to the embryonic lethality of conventional CBP knockout mice, we employed a tissue specific knockout mouse model (hGFAP-cre::CBPFl/Fl, mutant mouse) to achieve a homozygous deletion of CBP in neural precursor cells of the central nervous system.Our findings suggest that CBP plays a central role in brain size regulation, correct neural cell differentiation and neural precursor cell migration. We provide evidence that CBP is both important for stem cell viability within the ventricular germinal zone during embryonic development and for unhindered establishment of adult neurogenesis. Prominent histological findings in adult animals include a significantly smaller hippocampus with fewer neural stem cells. In the subventricular zone, we observe large cell aggregations at the beginning of the rostral migratory stream due to a migration deficit caused by impaired attraction from the CBP-deficient olfactory bulb. The cerebral cortex of mutant mice is characterized by a shorter dendrite length, a diminished spine number, and a relatively decreased number of mature spines as well as a reduced number of synapses.In conclusion, we provide evidence that CBP is important for neurogenesis, shaping neuronal morphology, neural connectivity and that it is involved in neuronal cell migration. These findings may help to understand the molecular basis of intellectual disability in RSTS patients and may be employed to establish treatment options to improve patients' quality of life.

Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease.

In Alzheimer's disease, BACE1 protease initiates the amyloidogenic processing of amyloid precursor protein (APP) that eventually results in synthesis of ß-amyloid (Aß) peptide. Aß deposition in turn causes accumulation of BACE1 in plaque-associated dystrophic neurites, thereby potentiating progressive Aß deposition once initiated. Since systemic pharmacological BACE inhibition causes adverse effects in humans, it is important to identify strategies that specifically normalize overt BACE1 activity around plaques. The microtubule-associated protein tau regulates axonal transport of proteins, and tau deletion rescues Aß-induced transport deficits in vitro. In the current study, long-term in vivo two-photon microscopy and immunohistochemistry were performed in tau-deficient APPPS1 mice. Tau deletion reduced plaque-associated axonal pathology and BACE1 accumulation without affecting physiological BACE1 expression distant from plaques. Thereby, tau deletion effectively decelerated formation of new plaques and reduced plaque compactness. The data revealed that tau reinforces Aß deposition, presumably by contributing to accumulation of BACE1 in plaque-associated dystrophies. Targeting tau-dependent mechanisms could become a suitable strategy to specifically reduce overt BACE1 activity around plaques, thereby avoiding adverse effects of systemic BACE inhibition.

Early defects in translation elongation factor 1α levels at excitatory synapses in α-synucleinopathy.

Cognitive decline and dementia in neurodegenerative diseases are associated with synapse dysfunction and loss, which may precede neuron loss by several years. While misfolded and aggregated α-synuclein is recognized in the disease progression of synucleinopathies, the nature of glutamatergic synapse dysfunction and loss remains incompletely understood. Using fluorescence-activated synaptosome sorting (FASS), we enriched excitatory glutamatergic synaptosomes from mice overexpressing human alpha-synuclein (h-αS) and wild-type littermates to unprecedented purity. Subsequent label-free proteomic quantification revealed a set of proteins differentially expressed upon human alpha-synuclein overexpression. These include overrepresented proteins involved in the synaptic vesicle cycle, ER-Golgi trafficking, metabolism and cytoskeleton. Unexpectedly, we found and validated a steep reduction of eukaryotic translation elongation factor 1 alpha (eEF1A1) levels in excitatory synapses at early stages of h-αS mouse model pathology. While eEF1A1 reduction correlated with the loss of postsynapses, its immunoreactivity was found on both sides of excitatory synapses. Moreover, we observed a reduction in eEF1A1 immunoreactivity in the cingulate gyrus neuropil of patients with Lewy body disease along with a reduction in PSD95 levels. Altogether, our results suggest a link between structural impairments underlying cognitive decline in neurodegenerative disorders and local synaptic defects. eEF1A1 may therefore represent a limiting factor to synapse maintenance.

Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau.

BACKGROUND: Augmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer's disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) study. METHODS: Twelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into Anle138b treatment and vehicle groups for 3 months. FDG-PET was repeated after treatment for 3 months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings. RESULTS: Tau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex - 53%, p < 0.001; hippocampus - 59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R = 0.92, p < 0.001). CONCLUSION: Late-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.

Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-ß Mouse Model.

Nonphysiologic overexpression of amyloid-ß (Aß) precursor protein in common transgenic Aß mouse models of Alzheimer disease likely hampers their translational potential. The novel AppNL-G-F mouse incorporates a mutated knock-in, potentially presenting an improved model of Alzheimer disease for Aß-targeting treatment trials. We aimed to establish serial small-animal PET of amyloidosis and neuroinflammation in AppNL-G-F mice as a tool for therapy monitoring. Methods:AppNL-G-F mice (20 homozygous and 21 heterogeneous) and 12 age-matched wild-type mice were investigated longitudinally from 2.5 to 10 mo of age with 18F-florbetaben Aß PET and 18F-GE-180 18-kDa translocator protein (TSPO) PET. Voxelwise analysis of SUV ratio images was performed using statistical parametric mapping. All mice underwent a Morris water maze test of spatial learning after their final scan. Quantification of fibrillar Aß and activated microglia by immunohistochemistry and biochemistry served for validation of the PET results. Results: The periaqueductal gray emerged as a suitable pseudo reference tissue for both tracers. Homozygous AppNL-G-F mice had a rising SUV ratio in cortex and hippocampus for Aß (+9.1%, +3.8%) and TSPO (+19.8%, +14.2%) PET from 2.5 to 10 mo of age (all P < 0.05), whereas heterozygous AppNL-G-F mice did not show significant changes with age. Significant voxelwise clusters of Aß deposition and microglial activation in homozygous mice appeared at 5 mo of age. Immunohistochemical and biochemical findings correlated strongly with the PET data. Water maze escape latency was significantly elevated in homozygous AppNL-G-F mice compared with wild-type at 10 mo of age and was associated with high TSPO binding. Conclusion: Longitudinal PET in AppNL-G-F knock-in mice enables monitoring of amyloidogenesis and neuroinflammation in homozygous mice but is insensitive to minor changes in heterozygous animals. The combination of PET with behavioral tasks in AppNL-G-F treatment trials is poised to provide important insights in preclinical drug development.

In vivo imaging reveals reduced activity of neuronal circuits in a mouse tauopathy model.

Pathological alterations of tau protein play a significant role in the emergence and progression of neurodegenerative disorders. Tauopathies are characterized by detachment of the tau protein from neuronal microtubules, and its subsequent aberrant hyperphosphorylation, aggregation and cellular distribution. The exact nature of tau protein species causing neuronal malfunction and degeneration is still unknown. In the present study, we used mice transgenic for human tau with the frontotemporal dementia with parkinsonism-associated P301S mutation. These mice are prone to develop fibrillar tau inclusions, especially in the spinal cord and brainstem. At the same time, cortical neurons are not as strongly affected by fibrillar tau forms, but rather by soluble tau forms. We took advantage of the possibility to induce formation of neurofibrillary tangles in a subset of these cortical neurons by local injection of preformed synthetic tau fibrils. By using chronic in vivo two-photon calcium imaging in awake mice, we were able for the first time to follow the activity of individual tangle-bearing neurons and compare it to the activity of tangle-free neurons over the disease course. Our results revealed strong reduction of calcium transient frequency in layer 2/3 cortical neurons of P301S mice, independent of neurofibrillary tangle presence. These results clearly point to the impairing role of soluble, mutated tau protein species present in the majority of the neurons investigated in this study.

Early and Longitudinal Microglial Activation but Not Amyloid Accumulation Predicts Cognitive Outcome in PS2APP Mice.

Neuroinflammation may have beneficial or detrimental net effects on the cognitive outcome of Alzheimer disease (AD) patients. PET imaging with 18-kDa translocator protein (TSPO) enables longitudinal monitoring of microglial activation in vivo. Methods: We compiled serial PET measures of TSPO and amyloid with terminal cognitive assessment (water maze) in an AD transgenic mouse model (PS2APP) from 8 to 13 mo of age, followed by immunohistochemical analyses of microglia, amyloid, and synaptic density. Results: Better cognitive outcome and higher synaptic density in PS2APP mice was predicted by higher TSPO expression at 8 mo. The progression of TSPO activation to 13 mo also showed a moderate association with spared cognition, but amyloidosis did not correlate with the cognitive outcome, regardless of the time point. Conclusion: This first PET investigation with longitudinal TSPO and amyloid PET together with terminal cognitive testing in an AD mouse model indicates that continuing microglial response seems to impart preserved cognitive performance.

Microglial response to increasing amyloid load saturates with aging: a longitudinal dual tracer in vivo µPET-study.

BACKGROUND: Causal associations between microglia activation and ß-amyloid (Aß) accumulation during the progression of Alzheimer's disease (AD) remain a matter of controversy. Therefore, we used longitudinal dual tracer in vivo small animal positron emission tomography (µPET) imaging to resolve the progression of the association between Aß deposition and microglial responses during aging of an Aß mouse model. METHODS: APP-SL70 mice (N = 17; baseline age 3.2-8.5 months) and age-matched C57Bl/6 controls (wildtype (wt)) were investigated longitudinally for 6 months using Aß (18F-florbetaben) and 18 kDa translocator protein (TSPO) µPET (18F-GE180). Changes in cortical binding were transformed to Z-scores relative to wt mice, and microglial activation relative to amyloidosis was defined as the Z-score difference (TSPO-Aß). Using 3D immunohistochemistry for activated microglia (Iba-1) and histology for fibrillary Aß (methoxy-X04), we measure microglial brain fraction relative to plaque size and the distance from plaque margins. RESULTS: Aß-PET binding increased exponentially as a function of age in APP-SL70 mice, whereas TSPO binding had an inverse U-shape growth function. Longitudinal Z-score differences declined with aging, suggesting that microglial response declined relative to increasing amyloidosis in aging APP-SL70 mice. Microglial brain volume fraction was inversely related to adjacent plaque size, while the proximity to Aß plaques increased with age. CONCLUSIONS: Microglial activity decreases relative to ongoing amyloidosis with aging in APP-SL70 mice. The plaque-associated microglial brain fraction saturated and correlated negatively with increasing plaque size with aging.

Consequences of Pharmacological BACE Inhibition on Synaptic Structure and Function.

Alzheimer's disease is the most prevalent neurodegenerative disorder among elderly persons. Overt accumulation and aggregation of the amyloid-ß peptide (Aß) is thought to be the initial causative factor for Alzheimer's disease. Aß is produced by sequential proteolytic cleavage of the amyloid precursor protein. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the initial and rate-limiting protease for the generation of Aß. Therefore, inhibiting BACE1 is considered one of the most promising therapeutic approaches for potential treatment of Alzheimer's disease. Currently, several drugs blocking this enzyme (BACE inhibitors) are being evaluated in clinical trials. However, high-dosage BACE-inhibitor treatment interferes with structural and functional synaptic plasticity in mice. These adverse side effects may mask the therapeutic benefit of lowering the Aß concentration. In this review, we focus on the consequences of BACE inhibition-mediated synaptic deficits and the potential clinical implications.

Comparison of 18F-T807 and 18F-THK5117 PET in a Mouse Model of Tau Pathology.

Positron-emission-tomography (PET) imaging of tau pathology has facilitated development of anti-tau therapies. While members of the arylquinoline and pyridoindole families have been the most frequently used tau radioligands so far, analyses of their comparative performance in vivo are scantly documented. Here, we conducted a head-to-head PET comparison of the arylquinoline 18FT807 and the pyridoindole 18FTHK5117 PET in a mouse model of tau pathology. PET recordings were obtained in groups of (N = 5-7) P301S and wild-type (WT) mice at 6 and 9 months of age. Volume-of-interest based analysis (standard-uptake-value ratio, SUVR) was used to calculate effect sizes (Cohen's d) for each tracer and age. Statistical parametric mapping (SPM) was used to assess regional similarity (dice coefficient) of tracer binding alterations for the two tracers. Immunohistochemistry staining of neurofibrillary tangles was performed for validation ex vivo. Significantly elevated 18F-T807 binding in the brainstem of P301S mice was already evident at 6 months (+14%, p < 0.01, d = 1.64), and increased further at 9 months (+23%, p < 0.001, d = 2.70). 18F-THK5117 indicated weaker increases and effect sizes at 6 months (+5%, p < 0.05, d = 1.07) and 9 months (+10%, p < 0.001, d = 1.49). Regional similarity of binding of the two tracers was high (71%) at 9 months. 18F-T807 was more sensitive than 18F-THK5117 to tau pathology in this model, although both tracers present certain obstacles, which need to be considered in the design of longitudinal preclinical tau imaging studies.

BACE1 inhibition more effectively suppresses initiation than progression of ß-amyloid pathology.

BACE1 is the rate-limiting protease in the production of synaptotoxic ß-amyloid (Aß) species and hence one of the prime drug targets for potential therapy of Alzheimer's disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early ß-amyloid pathology. The longitudinal approach allowed to assess the kinetics of individual plaques and associated presynaptic pathology, before and throughout treatment. BACE1 inhibition could not halt but slow down progressive ß-amyloid deposition and associated synaptic pathology. Notably, the data revealed that the initial process of plaque formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. This finding of particular susceptibility of plaque formation has profound implications to achieve optimal therapeutic efficacy for the prospective treatment of AD.

Time Courses of Cortical Glucose Metabolism and Microglial Activity Across the Life Span of Wild-Type Mice: A PET Study.

Contrary to findings in the human brain, 18F-FDG PET shows cerebral hypermetabolism of aged wild-type (WT) mice relative to younger animals, supposedly due to microglial activation. Therefore, we used dual-tracer small-animal PET to examine directly the link between neuroinflammation and hypermetabolism in aged mice. Methods: WT mice (5-20 mo) were investigated in a cross-sectional design using 18F-FDG (n = 43) and translocator protein (TSPO) (18F-GE180; n = 58) small-animal PET, with volume-of-interest and voxelwise analyses. Biochemical analysis of plasma cytokine levels and immunohistochemical confirmation of microglial activity were also performed. Results: Age-dependent cortical hypermetabolism in WT mice relative to young animals aged 5 mo peaked at 14.5 mo (+16%, P < 0.001) and declined to baseline at 20 mo. Similarly, cortical TSPO binding increased to a maximum at 14.5 mo (+15%, P < 0.001) and remained high to 20 mo, resulting in an overall correlation between 18F-FDG uptake and TSPO binding (R = 0.69, P < 0.005). Biochemical and immunohistochemical analyses confirmed the TSPO small-animal PET findings. Conclusion: Age-dependent neuroinflammation is associated with the controversial observation of cerebral hypermetabolism in aging WT mice.

Seeding and transgenic overexpression of alpha-synuclein triggers dendritic spine pathology in the neocortex.

Although misfolded and aggregated α-synuclein (α-syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how α-synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long-term in vivo imaging of apical dendrites was performed in mice overexpressing wild-type human α-synuclein. Additionally, intracranial injection of preformed α-synuclein fibrils was performed to induce cortical α-syn pathology. We find that α-synuclein overexpressing mice show decreased spine density and abnormalities in spine dynamics in an age-dependent manner. We also provide evidence for the detrimental effects of seeded α-synuclein aggregates on dendritic architecture. We observed spine loss as well as dystrophic deformation of dendritic shafts in layer V pyramidal neurons. Our results provide a link to the pathophysiology underlying dementia associated with synucleinopathies and may enable the evaluation of potential drug candidates on dendritic spine pathology in vivo.

Intraneuronal APP and extracellular Aß independently cause dendritic spine pathology in transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is thought to be caused by accumulation of amyloid-ß protein (Aß), which is a cleavage product of amyloid precursor protein (APP). Transgenic mice overexpressing APP have been used to recapitulate amyloid-ß pathology. Among them, APP23 and APPswe/PS1deltaE9 (deltaE9) mice are extensively studied. APP23 mice express APP with Swedish mutation and develop amyloid plaques late in their life, while cognitive deficits are observed in young age. In contrast, deltaE9 mice with mutant APP and mutant presenilin-1 develop amyloid plaques early but show typical cognitive deficits in old age. To unveil the reasons for different progressions of cognitive decline in these commonly used mouse models, we analyzed the number and turnover of dendritic spines as important structural correlates for learning and memory. Chronic in vivo two-photon imaging in apical tufts of layer V pyramidal neurons revealed a decreased spine density in 4-5-month-old APP23 mice. In age-matched deltaE9 mice, in contrast, spine loss was only observed on cortical dendrites that were in close proximity to amyloid plaques. In both cases, the reduced spine density was caused by decreased spine formation. Interestingly, the patterns of alterations in spine morphology differed between these two transgenic mouse models. Moreover, in APP23 mice, APP was found to accumulate intracellularly and its content was inversely correlated with the absolute spine density and the relative number of mushroom spines. Collectively, our results suggest that different pathological mechanisms, namely an intracellular accumulation of APP or extracellular amyloid plaques, may lead to spine abnormalities in young adult APP23 and deltaE9 mice, respectively. These distinct features, which may represent very different mechanisms of synaptic failure in AD, have to be taken into consideration when translating results from animal studies to the human disease.