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Background: Biomaterials from oral and nasal swabs provide, in theory, a potential resource for biomarker development. However, their diagnostic value has not yet been investigated in the context of Parkinson's disease (PD) and associated conditions. Objective: We have previously identified a PD‐specific microRNA (miRNA) signature in gut biopsies. In this work, we aimed to investigate the expression of miRNAs in routine buccal (oral) and nasal swabs obtained from cases with idiopathic PD and isolated rapid eye movement sleep behavior disorder (iRBD), a prodromal symptom that often precedes α‐synucleinopathies. We aimed to address their value as a diagnostic biomarker for PD and their mechanistic contribution to PD onset and progression. Methods: Healthy control cases (n = 28), cases with PD (n = 29), and cases with iRBD (n = 8) were prospectively recruited to undergo routine buccal and nasal swabs. Total RNA was extracted from the swab material, and the expression of a predefined set of miRNAs was quantified by quantitative real‐time polymerase chain reaction. Results: Statistical analysis revealed a significantly increased expression of hsa‐miR‐1260a in cases who had PD. Interestingly, hsa‐miR‐1260a expression levels correlated with diseases severity, as well as olfactory function, in the PD and iRBD cohorts. Mechanistically, hsa‐miR‐1260a segregated to Golgi‐associated cellular processes with a potential role in mucosal plasma cells. Predicted hsa‐miR‐1260a target gene expression was reduced in iRBD and PD groups. Conclusions: Our work demonstrates oral and nasal swabs as a valuable biomarker pool in PD and associated neurodegenerative conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: As opposed to other neurobehavioral disorders, epigenetic analyses and biomarkers are largely missing in the case of idiopathic restless legs syndrome (RLS). Objectives: Our aims were to develop a biomarker for RLS based on DNA methylation in blood and to examine DNA methylation in brain tissues for dissecting RLS pathophysiology. Methods: Methylation of blood DNA from three independent cohorts (n = 2283) and post‐mortem brain DNA from two cohorts (n = 61) was assessed by Infinium EPIC 850 K BeadChip. Epigenome‐wide association study (EWAS) results of individual cohorts were combined by random‐effect meta‐analysis. A three‐stage selection procedure (discovery, n = 884; testing, n = 520; validation, n = 879) established an epigenetic risk score including 30 CpG sites. Epigenetic age was assessed by Horvath's multi‐tissue clock and Shireby's cortical clock. Results: EWAS meta‐analysis revealed 149 CpG sites linked to 136 genes (P < 0.05 after Bonferroni correction) in blood and 23 CpG linked to 18 genes in brain (false discovery rate [FDR] < 5%). Gene‐set analyses of blood EWAS results suggested enrichments in brain tissue types and in subunits of the kainate‐selective glutamate receptor complex. Individual candidate genes of the brain EWAS could be assigned to neurodevelopmental or metabolic traits. The blood epigenetic risk score achieved an area under the curve (AUC) of 0.70 (0.67–0.73) in the validation set, comparable to analogous scores in other neurobehavioral disorders. A significant difference in biological age in blood or brain of RLS patients was not detectable. Conclusions: DNA methylation supports the notion of altered neurodevelopment in RLS. Epigenetic risk scores are reliably associated with RLS but require even higher accuracy to be useful as biomarkers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Accuracy of clinical diagnosis in neurodegenerative diseases is critically important for patient care and study recruitment. We aimed to investigate the precision of clinical diagnosis of various neurodegenerative conditions using neuropathological diagnosis for reference. Method: All 1310 autopsy cases between 1993 and 2017 from the Neurobiobank München (Munich, Germany) were screened for neurodegenerative diagnoses. Neuropathological diagnoses that occurred in at least five cases were included in the study. Real world clinical diagnoses were extracted from medical records of admitting hospitals in Germany and correlated with neuropathological diagnoses. Sensitivity, specificity and accuracy (using receiver operating characteristic (ROC) curves and area under the curve (AUC) analysis) of clinical diagnoses were calculated. Result: The study included 455 cases with neuropathologically diagnosed Alzheimer's disease (AD, n = 132), argyrophilic grain disease (AGD, n = 6), corticobasal degeneration (CBD, n = 20), frontotemporal lobar degeneration (FTLD, n = 47), Huntington's disease (HD, n = 22), Lewy body disease (LBD, n = 104), motor neuron disease (MND, n = 10), multiple system atrophy (MSA, n = 37) and progressive supranuclear palsy (PSP, n = 77). Clinical diagnoses in these cases comprised AD (n = 136), CBD (n = 17), Creutzfeldt‐Jakob disease (CJD, n = 6), dementia with Lewy bodies (DLB, n = 11), frontotemporal dementia (FTD, n = 44), HD (n = 23), MND (n = 20), MSA (n = 36), Parkinson's disease (PD, n = 92), PSP (n = 60) and vascular dementia (VD, n = 10). Figure 1 illustrates the relationship between clinical (left) and neuropathological diagnoses (right). Figure 2 shows sensitivity, specificity, ROC curves, AUCs including standard errors (SE) and 95% confidence intervals (CI) and p‐values for testing the null hypothesis AUC = 0.5 for clinical diagnoses. Conclusion: Clinical diagnoses of neurodegenerative diseases exhibited a wide span of sensitivity depending on the particular disease (0‐100%) while specificity was high for all clinical diagnoses (89.5‐100%). Accuracy of clinical diagnoses as determined with AUC analysis was very good (AUC>0.9) for HD, MND and MSA, good (AUC = 0.8‐0.9) for AD, DLB/PD and PSP, moderate (AUC = 0.7‐0.8) for FTD, poor (AUC = 0.51‐0.7) for CBD and bad/no discrimination capacity (AUC = 0.5) for AGD. Based on these findings, an increase of sensitivity of clinical diagnoses may be key to improve correct identification of neurodegenerative diseases. This may be possible through development and clinical implementation of molecular biomarkers that are able to indicate the causal proteinopathies of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Objectives: To identify the clinical characteristics of the subgroup of benign progressive supranuclear palsy with particularly long disease duration; to define neuropathological determinants underlying variability in disease duration in progressive supranuclear palsy.Methods: Clinical and pathological features were compared among 186 autopsy-confirmed cases with progressive supranuclear palsy with ≥10 years and shorter survival times.Results: The 45 cases (24.2%) had a disease duration of ≥10 years. The absence of ocular motor abnormalities within the first 3 years from disease onset was the only significant independent clinical predictor of longer survival. Histopathologically, the neurodegeneration parameters in each survival group were paralleled anatomically by the distribution of neuronal cytoplasmic inclusions, whereas the tufted astrocytes displayed anatomically an opposite severity pattern. Most interestingly, we found significantly less coiled bodies in those who survive longer, in contrast to patients with less favorable course.Interpretation: A considerable proportion of patients had a more "benign" disease course with ≥10 years survival. They had a distinct pattern and evolution of core symptoms compared to patients with short survival. The inverted anatomical patterns of astrocytic tau distribution suggest distinct implications of these cell types in trans-cellular propagation. The tempo of disease progression appeared to be determined mostly by oligodendroglial tau, where the high degree of oligodendroglial tau pathology might affect neuronal integrity and function on top of neuronal tau pathology. The relative contribution of glial tau should be further explored in cellular and animal models. ANN NEUROL 2022;92:637-649. [ABSTRACT FROM AUTHOR]

Misfolded α‐synuclein spreads along anatomically connected areas through the brain, prompting progressive neurodegeneration of the nigrostriatal pathway in Parkinson's disease. To investigate the impact of early stage seeding and spreading of misfolded α‐synuclein along with the nigrostriatal pathway, we studied the pathophysiologic effect induced by a single acute α‐synuclein preformed fibrils (PFFs) inoculation into the midbrain. Further, to model the progressive vulnerability that characterizes the dopamine (DA) neuron life span, we used two cohorts of mice with different ages: 2‐month‐old (young) and 5‐month‐old (adult) mice. Two months after α‐synuclein PFFs injection, we found that striatal DA release decreased exclusively in adult mice. Adult DA neurons showed an increased level of pathology spreading along with the nigrostriatal pathway accompanied with a lower volume of α‐synuclein deposition in the midbrain, impaired neurotransmission, rigid DA terminal composition, and less microglial reactivity compared with young neurons. Notably, preserved DA release and increased microglial coverage in the PFFs‐seeded hemisphere coexist with decreased large‐sized terminal density in young DA neurons. This suggests the presence of a targeted pruning mechanism that limits the detrimental effect of α‐synuclein early spreading. This study suggests that the impact of the pathophysiology caused by misfolded α‐synuclein spreading along the nigrostriatal pathway depends on the age of the DA network, reducing striatal DA release specifically in adult mice. [ABSTRACT FROM AUTHOR]

Background and purpose: Knowledge about the seizure prevalence in the whole symptomatic course, from disease onset to death, in neurodegenerative diseases (ND) is lacking. Therefore, the aim was to investigate seizure prevalence and associated clinical implications in neuropathologically diagnosed ND. Methods: Clinical records of cases from the Neurobiobank Munich, Germany, were analyzed. Neuropathological diagnoses of the assessed cases included Alzheimer disease (AD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Seizure prevalence during the whole symptomatic disease phase was assessed and compared amongst ND. Associations between first clinical symptom and seizure prevalence and between seizures and disease duration were examined. Results: In all, 454 patients with neuropathologically diagnosed ND and with available and meaningful clinical records were investigated (AD, n = 144; LBD, n = 103; PSP, n = 93; FTLD, n = 53; MSA, n = 36; CBD, n = 25). Seizure prevalence was 31.3% for AD, 20.0% for CBD, 12.6% for LBD, 11.3% for FTLD, 8.3% for MSA and 7.5% for PSP. Seizure prevalence was significantly higher in AD compared to FTLD (p = 0.005), LBD (p = 0.001), MSA (p = 0.005) and PSP (p < 0.001). No other significant differences regarding seizure prevalence were found between the studied ND. Cognitive first symptoms in ND were associated with an increased seizure prevalence (21.1% vs. 11.0% in patients without cognitive first symptoms) and motor first symptoms with a decreased seizure prevalence (10.3% vs. 20.5% in patients without motor first symptoms). Seizures were associated with a longer disease duration in MSA (12.3 vs. 7.0 years in patients without seizures; p = 0.017). Conclusions: Seizures are a clinically relevant comorbidity in ND, particularly in AD. Knowledge of the first clinical symptom in ND may allow for estimation of seizure risk. [ABSTRACT FROM AUTHOR]

Primary 4‐repeat tauopathies with frontotemporal lobar degeneration (FTLD) like Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration (CBD) show diverse cellular pathology in various brain regions. Besides shared characteristics of neuronal and oligodendroglial cytoplasmic inclusions of accumulated hyperphosphorylated tau protein (pTau), astrocytes in PSP and CBD contain pathognomonic pTau aggregates — hence, lending the designation tufted astrocytes (TA) or astrocytic plaques (AP), respectively. pTau toxicity is most commonly assigned to neurons, whereas the implications of astrocytic pTau for maintaining neurotransmission within the tripartite synapse of human brains is not well understood. We performed immunofluorescent synapse labeling and automated puncta quantification in the medial frontal gyrus (MFG) and striatal regions from PSP and CBD postmortem samples to capture morphometric synaptic alterations. This approach indicated general synaptic losses of both, excitatory and inhibitory bipartite synapses in the frontal cortex of PSP cases, whereas in CBD lower synapse densities were only related to astrocytic plaques. In contrast to tufted astrocytes in PSP, affected astrocytes in CBD could not preserve synaptic integrity within their spatial domains, when compared to non‐affected internal astrocytes or astrocytes in healthy controls. These findings suggest a pTau pathology‐associated role of astrocytes in maintaining connections within neuronal circuits, considered as the microscopic substrate of cognitive dysfunction in CBD. By contrasting astrocytic‐synaptic associations in both diseases, we hereby highlight astrocytic pTau as an important subject of prospective research and as a potential cellular target for therapeutic approaches in the primary tauopathies PSP and CBD. [ABSTRACT FROM AUTHOR]

Background and purpose: Clinical diagnostic criteria for neurodegenerative diseases have been framed based on clinical phenomenology. However, systematic knowledge about the first reported clinical symptoms in neurodegenerative diseases is lacking. Therefore, the aim was to determine the prevalence and clinical implications of the first clinical symptom (FS) as assessed by medical history in neuropathologically proven neurodegenerative diseases. Methods: Neuropathological diagnoses from the Neurobiobank Munich, Germany, were matched with clinical records for analyses of the diagnostic and prognostic values of FSs. Results: In all, 301 patients with the neuropathological diagnoses Alzheimer disease (AD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD) including the neuropathologically indistinguishable clinical phenotypes Parkinson disease and dementia with Lewy bodies, multiple system atrophy (MSA) and corticobasal degeneration (CBD) were studied. Memory disturbance was the most common FS in AD (34%), FTLD (19%) and LBD (26%), gait disturbance in PSP (35%) and MSA (27%) and aphasia and personality changes in CBD (20%, respectively). In a model adjusting for prevalence in the general population, AD was predicted by memory disturbance in 79.0%, aphasia in 97.2%, personality changes in 96.0% and by cognitive disturbance in 99.0%. Gait disturbance and tremor predicted LBD in 54.6% and 97.3%, coordination disturbance MSA in 59.4% and dysarthria FTLD in 73.0%. Cognitive FSs were associated with longer survival in AD (12.0 vs. 5.3 years; p < 0.001) and FTLD (8.2 vs. 4.1 years; p = 0.005) and motor FSs with shorter survival in PSP (7.2 vs. 9.7; p = 0.048). Conclusions: Assessing FSs in neurodegenerative diseases may be beneficial for accuracy of diagnosis and prognosis and thereby may improve clinical care and precision of study recruitment. [ABSTRACT FROM AUTHOR]

Background: β‐amyloid PET (Aβ‐PET) is an important tool for quantification of amyloidosis in the brain of suspected Alzheimer's disease (AD) patients and transgenic AD mouse models. Despite the excellent correlation of Aβ‐PET with gold standard immunohistochemical assessments, the relative contributions of fibrillar and non‐fibrillar Aβ components to the in vivo Aβ‐PET signal remain unclear. Thus, we obtained two murine cerebral amyloidosis models that present with distinct Aβ plaque compositions and performed regression analysis between immunohistochemistry and Aβ PET to determine the biochemical contributions to Aβ‐PET signal in vivo. Method: We investigated groups of AppNL‐G‐F and APPPS1 mice three, six and 12 months of age by longitudinal [18F]‐florbetaben Aβ‐PET and with immunohistochemical analysis of the fibrillar and total Aβ burdens. We then applied group level inter‐modality regression models using age and genotype matched sets of fibrillar/ non‐fibrillar Aβ data (predictors) and Aβ‐PET results (outcome) for both transgenic models. An independent group of double‐hit APPPS1 mice with dysfunctional microglia due to knock‐out of triggering receptor expression on myeloid cells 2 (Trem2‐/‐) served for validation and evaluation of translational impact. Result: Neither fibrillar nor non‐fibrillar Aβ content alone sufficed to explain the Aβ‐PET findings in either transgenic AD model (Figure 1). A regression model compiling fibrillar and non‐fibrillar Aβ together with the estimate of individual heterogeneity and age at scanning could explain a 93% of variance of the Aβ‐PET signal (p<0.001; Figure 2). Fibrillar Aβ burden had a 16‐fold higher contribution to the Aβ‐PET signal when compared to non‐fibrillar Aβ. However, given the relatively greater abundance of non‐fibrillar Aβ, we estimate that non‐fibrillar Aβ produced 79±25% of the net in vivo Aβ‐PET signal in AppNL‐G‐F mice, and 25±12% in the APPPS1 mice. Corresponding results in groups of APPPS1/Trem2‐/‐ and APPPS1/Trem2+/+ mice validated the calculated regression factors and revealed that the altered fibrillarity due to Trem2 knockout impacts the Aβ‐PET signal (Figure 3). Conclusion: Taken together, the in vivo Aβ‐PET signal derives from the composite of fibrillar and non‐fibrillar Aβ plaque components. While fibrillar Aβ has inherently higher PET tracer binding, the greater abundance of non‐fibrillar Aβ plaque in AD model mice contributes importantly to the PET signal. [ABSTRACT FROM AUTHOR]

Microglia activation is the brain's major immune response to amyloid plaques in Alzheimer's disease (AD). Both cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2), a biomarker of microglia activation, and microglia PET are increased in AD; however, whether an increase in these biomarkers is associated with reduced amyloid‐beta (Aβ) accumulation remains unclear. To address this question, we pursued a two‐pronged translational approach. Firstly, in non‐demented and demented individuals, we tested CSF sTREM2 at baseline to predict (i) amyloid PET changes over ∼2 years and (ii) tau PET cross‐sectionally assessed in a subset of patients. We found higher CSF sTREM2 associated with attenuated amyloid PET increase and lower tau PET. Secondly, in the AppNL‐G-F mouse model of amyloidosis, we studied baseline 18F‐GE180 microglia PET and longitudinal amyloid PET to test the microglia vs. Aβ association, without any confounding co‐pathologies often present in AD patients. Higher microglia PET at age 5 months was associated with a slower amyloid PET increase between ages 5‐to‐10 months. In conclusion, higher microglia activation as determined by CSF sTREM2 or microglia PET shows protective effects on subsequent amyloid accumulation. Synopsis: TREM2 is a protein almost exclusively expressed by microglia in the brain. This study investigates the association between soluble TREM2 (sTREM2) levels in cerebrospinal fluid and the longitudinal Aβ accumulation in human and mouse. In patients with Aβ pathology, higher cerebrospinal fluid (CSF) levels of sTREM2 are associated with lower rates of Aβ accumulation.Higher CSF sTREM2 levels are associated with lower neurofibrillary tangles.In the Aβ mouse model, higher microglia activation at baseline is associated with lower rates of Aβ accumulation between 5 and 10 months of age, when Aβ deposition primarily takes place. [ABSTRACT FROM AUTHOR]

Background: All clinical BACE‐inhibitor trials for the treatment of Alzheimer´s Disease have failed due to insufficient efficacy or side effects like worsening of cognitive symptoms. The latter could have been the result of the inhibition of BACE at the synapse where it is expressed in high amounts. We have previously shown that prolonged inhibition of BACE interferes with structural and functional synaptic plasticity (Filser et al. Biol. Psych 2015, Blume et al. Front. Aging Neurosci. 2018), most likely due to the diminished processing of the physiological BACE substrate Seizure protein 6 (Sez6, Zhu et al. Biol. Psych. 2018), which is exclusively processed by BACE1 and it is required for dendritic spine plasticity. The aim of the current study was to elucidate the effects of selective BACE1 inhibitors on dendritic spine plasticity at a dose that affects Sez6 cleavage to various degrees but not completely. Method: By using longitudinal in vivo two‐photon microscopy, we investigated the effect on dendritic spine dynamics of pyramidal layer V neurons in the somatosensory cortex in mice treated with 2 novel highly selective BACE1 inhibitors developed at Shionogi in comparison to Elenbecestat which reduce soluble Sez6 to 27% (Elenbecastat), 17% (Shionogi Compound 1) and 39% (Shionogi Compound2) of baseline levels in untreated animals. For the detection of the soluble Sez6 ectodomain, the BACE cleavage product from full‐length Sez6, Western blot analysis was performed using a highly specific Sez6 antibody generated in the lab of Stefan Lichtenthaler (Pigoni et al. Mol. Neurodeg. 2016). Result: We observed that BACE1 selective inhibitors do not alter dendritic spine density and plasticity in cortical neurons if at least 27% of soluble Sez6 remains. In detail, the density of gained and lost spines does not change under the treatment with Shionogi Compound 2 or Elenbecastat. Also, no differences in the stability of dendritic spines were found during treatment with these two compounds. With Compound 1 however, a significant spine loss occurs after 21 days of treatment. Conclusion: Selective BACE1 inhibitors do not alter dendritic spine plasticity in mice if dosing reduces synaptic BACE1 cleavage of Sez6 not below 27% of baseline soluble Sez6 levels. BACE1 selective inhibitors may be potential novel candidates for clinical trials treating AD if dosing is carefully adjusted to the amount of Sez6 cleavage, which can be easily monitored during the first weeks of treatment. [ABSTRACT FROM AUTHOR]

Summary: Objective: Almost half of the cases of Cushing's disease (CD) tumours carry recurrent activating somatic mutations in the ubiquitin‐specific protease eight gene (USP8). The USP8 mutational status could predict remission in patients with CD, so our objective was to correlate the presence of somatic USP8 mutations with the rate of recurrence after transsphenoidal surgery (TSS) retrospectively. Design: Biochemical, radiological and clinical data were retrospectively assessed in 48 patients. USP8 mutational status was determined from corticotroph tumour samples. Association between USP8 mutational status, remission and recurrence was investigated. Patients: Patients with Cushing's disease from a single‐centre cohort who underwent TSS between 1991 and 2012. Measurements: Long‐term remission and recurrence rate after TSS with at least 6 months follow‐up. Biochemical, radiological and clinical data, including sex, age at diagnosis, tumour size and pre‐operative hormonal levels. USP8 mutational status. Results: Patients with USP8 mutant corticotroph tumours (18 of 48; 37%) were diagnosed significantly earlier (mean ± SD 46 ± 10 years vs 53 ± 11 years; P = 0.028) and presented with higher pre‐operative 24‐hour urinary‐free cortisol levels (median IQR μg/24 hours 1174.0, 1184.5 vs 480.0, 405.3; P = 0.045). The incidence of recurrence in a 10‐year follow‐up was significantly higher in patients with USP8 mutant tumours after the initial remission (58% vs 18% P = 0.026). Recurrence appeared significantly earlier in these patients (months 70, 44‐97 95% CI vs 102, 86‐119 95% CI; P = 0.019). Conclusion: Recurrence appears to be more frequent and earlier after TSS in patients with USP8 mutant corticotroph tumours. [ABSTRACT FROM AUTHOR]

Background: In vivo assessment of neuroinflammation by 18 kDa translocator protein positron‐emission‐tomography (TSPO‐PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO expression in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on TSPO expression in amyloid and tau mouse models and wild‐type (WT). Method: Longitudinal 18F‐GE‐180 TSPO‐PET (18F‐GE180) data of AppNL‐G‐F (amyloid model), P301S (tau model) and C57Bl/6 (WT) mice were evaluated between two and twelve months of age. AppNL‐G‐F received additional longitudinal amyloid‐PET (Aβ‐PET; 18F‐florbetaben). Immunohistochemistry also served for validation of microglial (Iba1, CD68) and tau (AT8) markers at the terminal time point. PET and immunohistochemistry were quantified in cortical regions and compared by linear mixed models (PET) and analysis of variance (immunohistochemistry) between male and female mice. Result: The amyloid model AppNL‐G‐F revealed a distinct cortical increase of TSPO‐PET values from 2.5 to 10 months in female mice (+31%), whereas male mice only increased slightly (+6%). The linear mixed model indicated a significant sex x time interaction (T=‐2.953, b/SE=‐0.011/0.004, p=0.0048, Figure 1A), validated by Iba1 and CD68 immunohistochemistry (Figure 2). Aβ‐PET values in the same AppNL‐G‐F mice indicated no significant time x sex interaction (T=0.425, b/SE=0.001/0.003, p=0.673, Figure 3). The P301S tau model showed strong cortical increases of TSPO‐PET from 2 to 8.5 months of age (female: +32%, male: +36%) but no significant sex x time interaction (T=‐0.671, b/SE=‐0.003/0.005, p=0.504, Figure 1B) and no differences in Iba1, CD68 or AT8 were observed. TSPO‐PET values in WT mice indicated an increase with time (female: +23%, male +4%) and a significant time x sex interaction was found (T=‐4.171, b/SE=‐0.009/0.002, p<0.001, Figure 1C). Conclusion: Female mice indicate a sex dependent elevation of glial activation in response to amyloidosis but not to tau pathology which could be related to differences in sex dependency of microglial activation pathways in presence of both proteins. Sex requires attention when microglia activation is evaluated in mouse models of Alzheimer's disease and requires detailed studies in human disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Dynamic synapses facilitate activity-dependent remodeling of neural circuits, thereby providing the structural substrate for adaptive behaviors. However, the mechanisms governing dynamic synapses in adult brain are still largely unknown. Here, we demonstrate that in the cortex of adult amyloid precursor protein knockout ( APP- KO) mice, spine formation and elimination were both reduced while overall spine density remained unaltered. When housed under environmental enrichment, APP- KO mice failed to respond with an increase in spine density. Spine morphology was also altered in the absence of APP. The underlying mechanism of these spine abnormalities in APP- KO mice was ascribed to an impairment in D-serine homeostasis. Extracellular D-serine concentration was significantly reduced in APP- KO mice, coupled with an increase of total D-serine. Strikingly, chronic treatment with exogenous D-serine normalized D-serine homeostasis and restored the deficits of spine dynamics, adaptive plasticity, and morphology in APP- KO mice. The cognitive deficit observed in APP- KO mice was also rescued by D-serine treatment. These data suggest that APP regulates homeostasis of D-serine, thereby maintaining the constitutive and adaptive plasticity of dendritic spines in adult brain. [ABSTRACT FROM AUTHOR]

Background: BACE1‐inhibitor trials for the treatment of Alzheimer´s Disease (AD) have failed due to insufficient efficacy or side effects like cognitive worsening. However, the scientific evidence to date suggests that BACE1‐inhibition could be an effective preventative measure if applied early enough and in the correct dose. Preclinical studies have associated strong BACE1‐inhibition with decreased dendritic spine density in the cerebral cortex of wildtype mice (GFP‐M) only. Method: We investigated dose‐dependent effects of BACE1‐inhibition on hippocampal dendritic spine dynamics in the APP knock‐in mouse line for the first time. We conducted in vivo two‐photon microscopy in the stratum oriens of hippocampal CA1 neurons in 3.5‐month‐old AppNL‐G‐FGFP‐M mice over 6 weeks to monitor the effect of Bace1 inhibition (NB‐360) in low and high doses on dendritic spine plasticity. Results: Structural spine plasticity is already impaired in CA1 neurons in untreated AppNL‐G‐F mice of this early age. Interestingly, prolonged high‐dose but not low‐dose BACE1‐inhibition was found to enhance spine formation and did not cause spine loss as observed in wildtype control mice. Conclusion: In an early stage of amyloid pathology in a transgenic beta‐amyloid mouse model, BACE1‐inhibition successfully holds the progressive changes in dendritic spine plasticity in hippocampal CA1 neurons. [ABSTRACT FROM AUTHOR]

Background: Lewy body pathology (LBP) occurs in a substantial portion of individuals with autosomal dominant (ADAD) and sporadic Alzheimer disease (sAD) (Ringman, 2016; Cairns, 2015; Leverenz, 2007; Lippa, 1998). Whereas other non‐AD pathologies are frequent in sAD, LBP seems to be the most common co‐pathology in the relatively young ADAD population (Cairns, 2015). Knowledge of clinical and genetic characteristics of LBP in both ADAD and sAD is incomplete. Method: Data from the National Alzheimer's Coordinating Center, the Dominantly Inherited Alzheimer Network, the Queen Square Brain Bank at University College London and the Neurobiobank Munich were leveraged to compare individuals with ADAD and neuropathologically diagnosed sAD with and without LBP. Chi‐squared and Student's t‐test were used for comparison of categorical and continuous variables respectively. Result: The study included 139 ADAD and 4661 sAD autopsy cases. LBP occurred in 59% of ADAD and 38% of sAD cases. LBP was associated with a longer survival in both ADAD (10.1 vs. 8.6 years, p=0.024) and sAD (10.5 vs. 10.2 years, p=0.016). Memory disturbance occurred more frequently as the first clinical AD symptom in both AD variants when LBP was present (ADAD: 90 vs. 65%, p=0.005; sAD: 78 vs. 71%, p<0.001). In both ADAD and sAD, the presence of at least one APOE e4 allele was more common in individuals with LBP (ADAD: 40 vs. 21%, p=0.047; sAD: 57 vs. 46%, p<0.001). In ADAD, frequency of LBP did not differ between individuals with PSEN1 and APP mutations. Conclusion: In this investigation of 139 ADAD and 4661 sAD autopsy cases, LBP occurred in about 60% with ADAD and 40% with sAD. In both ADAD and sAD, the presence of LBP was associated with longer survival, higher frequency of memory disturbance as the first AD symptom and positive APOE e4 status. Further study of these associations may increase our understanding of the role of LBP in AD. [ABSTRACT FROM AUTHOR]

In suspected grade II gliomas, three distinct patterns of time-activity curves (TAC) on O-(2-[18F]fluoroethyl)-1-tyrosine (18F-FET) positron emission tomography (PET) have been delineated ( i) increasing TAC homogeneously throughout the tumor, and decreasing TAC, ( ii) either homogeneously throughout the tumor or ( iii) only focally within otherwise increasing TAC patterns. Increasing TAC was associated with low-grade histology and decreasing TAC with high-grade histology. This prospective study analyzed whether these patterns correlate with distinct biological tumor subtypes and differential outcome. 18F-FET PET-guided biopsies were used for stepwise histopathological evaluation. Molecular-genetic evaluation included O6-methylguanine-DNA methyltransferase ( MGMT) promoter methylation, isocitrate dehydrogenase ( IDH1/2) mutational and 1p/19q codeletion status. Progression-free survival (PFS) was estimated with the Kaplan-Meier method. Prognostic factors were obtained from multivariate regression models. 98 adult patients were included. Homogeneous increasing, focal decreasing and homogeneous decreasing TAC were seen in 51, 19 and 28 patients. The corresponding 1-year (2-years) PFS were 92% (85%), 89% (51%) and 50% (28%; p = 0.002). IDH1/2 mutations were more frequent in tumors with homogeneous increasing (90%) and focal decreasing (79%) TAC, but were rare in those exhibiting homogeneous decreasing TAC (25%; p < 0.001). Overall, TAC patterns, IDH1/2 mutational and 1p/19q codeletion status were powerful and independent prognostic factors. Dynamic 18F-FET PET might be an important and independent imaging biomarker for patients with suspected WHO grade II gliomas and offers perspectives for stratified diagnostic and therapeutic strategies. Tumors with focal decreasing TAC need highly targeted surgical interventions to avoid undergrading and undertreatment. [ABSTRACT FROM AUTHOR]

Mutations in presenilins ( PS1 and PS2) account for the vast majority of early onset familial Alzheimer's disease cases. Beside the well investigated role of presenilins as the catalytic unit in γ-secretase complex, their involvement in regulation of intracellular calcium homeostasis has recently come into more focus of Alzheimer's disease research. Here we report that the overexpression of PS1 full-length holoprotein forms, in particular familial Alzheimer's disease-causing forms of PS1, result in significantly attenuated calcium release from thapsigargin- and bradykinin-sensitive stores. Interestingly, treatment of HEK293 cells with γ-secretase inhibitors also leads to decreased amount of calcium release from endoplasmic reticulum (ER) accompanying elevated PS1 holoprotein levels. Similarly, the knockdown of PEN-2 which is associated with deficient PS1 endoproteolysis and accumulation of its holoprotein form also leads to decreased ER calcium release. Notably, we detected enhanced PS1 holoprotein levels also in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. Taken together, the conditions in which the amount of full length PS1 holoprotein is increased result in reduction of calcium release from ER. Based on these results, we propose that the disturbed ER calcium homeostasis mediated by the elevation of PS1 holoprotein levels may be a contributing factor to the pathogenesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2011) 119, 1064-1073. Abstract Mutations in presenilins are the major cause of familial Alzheimer's disease (FAD), leading to impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Presenilins are the catalytic subunits of γ-secretase, which itself is critically involved in the processing of amyloid precursor protein to release neurotoxic amyloid β (Aβ). Besides Aβ generation, there is growing evidence that presenilins play an essential role in the formation and maintenance of synapses. To further elucidate the effect of presenilin1 (PS1) on synapses, we performed longitudinal in vivo two-photon imaging of dendritic spines in the somatosensory cortex of transgenic mice over-expressing either human wild-type PS1 or the FAD-mutated variant A246E (FAD-PS1). Interestingly, the consequences of transgene expression were different in two subtypes of cortical dendrites. On apical layer 5 dendrites, we found an enhanced spine density in both mice over-expressing human wild-type presenilin1 and FAD-PS1, whereas on basal layer 3 dendrites only over-expression of FAD-PS1 increased the spine density. Time-lapse imaging revealed no differences in kinetically distinct classes of dendritic spines nor was the shape of spines affected. Although γ-secretase-dependent processing of synapse-relevant proteins seemed to be unaltered, higher expression levels of ryanodine receptors suggest a modified Ca2+ homeostasis in PS1 over-expressing mice. However, the conditional depletion of PS1 in single cortical neurons had no observable impact on dendritic spines. In consequence, our results favor the view that PS1 influences dendritic spine plasticity in a gain-of-function but γ-secretase-independent manner. [ABSTRACT FROM AUTHOR]

Aggregated α-synuclein (α-syn) is a characteristic pathological finding in Parkinson's disease and related disorders, such as dementia with Lewy bodies. Recent evidence suggests that α-syn oligomers represent the principal neurotoxic species; however, the pathophysiological mechanisms are still not well understood. Here, we studied the neurophysiological effects of various biophysically- characterized preparations of a-syn aggregates on excitatory synaptic transmission in autaptic neuronal cultures. Nanomolar concentrations of large α-syn oligomers, generated by incubation with organic solvent and Fe3+ ions, were found to selectivity enhance evoked a-amino- 3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-receptor, but not NMDA-receptor, mediated synaptic transmission within minutes. Moreover, the analysis of spontaneous AMPAreceptor- mediated miniature synaptic currents revealed an augmented frequency. These results collectively indicate that large α-syn oligomers alter both pre- and post-synaptic mechanisms of AMPA-receptor-mediated synaptic transmission. The augmented excitatory synaptic transmission may directly contribute to nerve cell death in synucleinopathies. Indeed, already low micromolar glutamate concentrations were found to be toxic in primary cultured neurons incubated with large α-syn oligomers. In conclusion, large α-syn oligomers enhance both pre- and post-synaptic AMPAreceptor- mediated synaptic transmission, thereby aggravating intracellular calcium dyshomeostasis and contributing to excitotoxic nerve cell death in synucleinopathies. [ABSTRACT FROM AUTHOR]

Protoporphyrin IX (PpIX) produced from exogenous, orally administered 5-aminolevulinic acid (ALA) displays high tumor-selective uptake and is being successfully employed for fluorescence-guided resection (FGR) of human malignant gliomas. Furthermore, the phototoxicity of PpIX can be utilized for photodynamic therapy (PDT) of brain tumors, which has been shown previously. Here, the absolute PpIX concentration in human brain tissue was investigated following oral ALA administration (20 mg kg b.w.). An extraction procedure was used to quantify PpIX in macroscopic tissue samples, weighing 0.013-0.214 g, obtained during FGR. The PpIX concentration was significantly higher in vital grade IV tumors (5.8 ± 4.8 μ, mean ± SD, range 0-28.2 μ, = 8) as compared with grade III tumors (0.2 ± 0.4 μ, mean ± SD, range 0-0.9 μ, = 4). There was also a large heterogeneity within grade IV tumors with PpIX displaying significantly lower levels in infiltration zones and necrotic regions as compared with vital tumor parts. The average PpIX concentration in vital grade IV tumor parts was in the range previously shown sufficient for PDT-induced tissue damage following irradiation. However, the feasibility of PDT for grade III brain tumors and for grade IV brain tumors displaying mainly necrotic tissue areas without solid tumor parts needs to be further investigated. [ABSTRACT FROM AUTHOR]

Background: In the neurodegenerative conditions Alzheimer disease (AD), Lewy body disease (LBD) including the neuropathologically indistinguishable Parkinson disease and dementia with Lewy bodies, frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) figures for seizure risk are inconsistent, rare or lacking. This is particular true if neuropathologically confirmed diagnoses are stipulated. Therefore, our goal was to determine the lifetime risk for epileptic seizures and to investigate associated clinical parameters in neuropathologically diagnosed neurodegenerative diseases. Method: Cases from the Neurobiobank Munich, Germany, were matched with information from clinical files regarding the occurrence of epileptic seizures. The aforementioned diseases were compared for lifetime seizure risk. The predictive value of the first clinical symptom regarding lifetime risk for seizures was analyzed and associations between the occurrence of seizures and survival was investigated. Result: We analyzed 454 neuropathologically diagnosed cases with sufficient clinical data available. 144 had AD, 103 LBD, 93 PSP, 53 FTLD, 36 MSA, and 25 CBD. Lifetime risk for epileptic seizures was 31.3% in AD, 20.0% in CBD, 12.6% in LBD, 11.3% in FTLD, 8.3% in MSA and 7.5% in PSP. Patients with AD had a statistically significantly higher lifetime risk for seizures compared to patients with FTLD (p=0.005), LBD (p=0.001), MSA (p=0.005) and PSP (p<0.001). An increased lifetime seizure risk was found in patients with cognitive first symptoms when compared to those with non‐cognitive first symptoms (21.1% vs. 11.0%). A decreases lifetime risk for seizures was observed in cases with motor first symptoms when compared to those with non‐motor first symptoms (10.3% vs. 20.5%). MSA patients with seizures survived longer when compared to those without (12.3 vs. 7.0 years; p = 0.017). Conclusion: In this clinical neuropathological correlation study, nearly every third AD patient and approximately every fifth patient with a neurodegenerative disease experienced epileptic seizures in the disease course. Therefore, epileptic seizures are an important comorbidity in neurodegenerative conditions, in particular in AD. Assessment of the first clinical symptom may improve early estimation of the lifetime seizure risk in the studied neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Consecutive cleavages of amyloid precursor protein (APP) generate APP intracellular domain (AICD). Its cellular function is still unclear. In this study, we investigated the functional role of AICD in cellular Ca2+ homeostasis. We could confirm previous observations that endoplasmic reticulum Ca2+ stores contain less calcium in cells with reduced APP γ-secretase cleavage products, increased AICD degradation, reduced AICD expression or in cells lacking APP. In addition, we observed an enhanced resting cytosolic calcium concentration under conditions where AICD is decreased or missing. In view of the reciprocal effects of Ca2+ on mitochondria and of mitochondria on Ca2+ homeostasis, we analysed further the cellular ATP content and the mitochondrial membrane potential. We observed a reduced ATP content and a mitochondrial hyperpolarisation in cells with reduced amounts of AICD. Blockade of mitochondrial oxidative phosphorylation chain in control cells lead to similar alterations as in cells lacking AICD. On the other hand, substrates of Complex II rescued the alteration in Ca2+ homeostasis in cells lacking AICD. Based on these observations, our findings indicate that alterations observed in endoplasmic reticulum Ca2+ storage in cells with reduced amounts of AICD are reciprocally linked to mitochondrial bioenergetic function. [ABSTRACT FROM AUTHOR]

The physiological function of the cellular prion protein (PrPC) is still under intense investigation. It has been suggested that PrPC has a protective role in neuronal cells, particularly against environmental stress caused by reactive oxygen species (ROS). Here we analysed the acute effect of a major ROS, hydrogen peroxide (H2O2), on intracellular calcium homeostasis in cultured cerebellar granule cells and immortalized hippocampal neuronal cells. Both neuronal cell culture models showed that the rise in intracellular calcium following application of H2O2 was strongly dependent on the presence of PrPC. Moreover, the N-terminal octapeptide repeats of PrPC were required for this effect, because neuronal cells expressing a PrPC lacking the N-terminus resembled the PrPC-deficient phenotype. Neurones deficient of fyn kinase, or pharmacological inhibition of fyn, also abrogated the calcium response to H2O2 treatment, indicating that fyn activation is a critical step within the PrPC signalling cascade. Finally, we identified a possible role of this PrPC signalling pathway in the neuroprotective response of PrPC to oxidative stress. In conclusion, we put forward the hypothesis that PrPC functions as a sensor for H2O2, thereby activating a protective signalling cascade involving fyn kinase that leads to calcium release from intracellular stores. [ABSTRACT FROM AUTHOR]

Both tumors underwent 450K-methylation analysis that identified posterior fossa ependymomas, group A (EPN PFA) (0.67 (1) and 0.99 (2), respectively), which have aggressive behavior and bad outcomes. Therefore, the 450K-methylation profiling strongly suggests that the initial manifestation represented like the second one an anaplastic ependymoma and not a medulloblastoma, thus prompting to consider methylation profiling for all pediatric small blue round cell tumors. Still, this case emphasizes the relevance and importance of molecular analyses of pediatric brain tumors as (1) histological assessment only can be misleading, particularly in small blue round cell tumors and (2) different tumor entities in the same patient can be clearly distinguished. [Extracted from the article]

Previous neurophysiological studies on prion protein deficient ( Prnp –/–) mice have revealed a significant reduction of slow afterhyperpolarization currents (s IAHP) in hippocampal CA1 pyramidal cells. Here we aim to determine whether loss of PrPC. directly affects the potassium channels underlying s IAHP or if s IAHP is indirectly disturbed by altered intracellular Ca2+ fluxes. Patch-clamp measurements and confocal Ca2+ imaging in acute hippocampal slice preparations of Prnp –/– mice compared to littermate control mice revealed a reduced Ca2+ rise in CA1 neurons lacking PrPC following a depolarization protocol known to induce s IAHP. Moreover, we observed a reduced Ca2+ influx vial-type voltage gated calcium channels (VGCCs). No differences were observed in the protein expression of the pore forming α1 subunit of VGCCs Prnp –/– mice. Surprisingly, the β2 subunit, critically involved in the transport of the α1 subunit to the plasma membrane, was found to be up-regulated in knock out hippocampal tissue. On mRNA level however, no differences could be detected for the α1C, D and β2–4 subunits. In conclusion our data support the notion that lack of PrPC. does not directly affect the potassium channels underlying s IAHP, but modulates these channels due to its effect on the intracellular free Ca2+ concentration via a reduced Ca2+ influx throughl-type VGCCs. [ABSTRACT FROM AUTHOR]

The Alzheimer's diseaseß-amyloid precursor protein (APP) is a member of a larger gene family that includes the amyloid precursor-like proteins, termed APLP1 and APLP2. We previously documented that APLP2-/-APLP1-/- and APLP2-/-APP-/- mice die postnatally, while APLP1-/-APP-/- mice and single mutants were viable. We now report that mice lacking all three APP/APLP family members survive through embryonic development, and die shortly after birth. In contrast to double-mutant animals with perinatal lethality, 81%of triple mutants showed cranial abnormalities. In 68%of triple mutants, we observed cortical dysplasias characterized by focal ectopic neuroblasts that had migrated through the basal lamina and pial membrane, a phenotype that resembles human type II lissencephaly. Moreover, at E18.5 triple mutants showed a partial loss of cortical Cajal Retzius (CR) cells, suggesting that APP/APLPs play a crucial role in the survival of CR cells and neuronal adhesion. Collectively, our data reveal an essential role for APP family members in normal brain development and early postnatal survival. [ABSTRACT FROM AUTHOR]

The prion protein (PrPC ) has a primary role in the pathogenesis of transmissible spongiform encephalopathies. Here we analysed in detail the effect of recombinant PrPC and N- and C-terminal fragments of PrPC on the whole-cell current amplitude through voltage-gated calcium channels (VGCCs) of cultured wild-type cerebellar granule cells. With the application of full-length recombinant PrPC (50–500 n m ), a highly significant reduction of the whole-cell current amplitude was observed in a dose-dependent manner. Amplitude reduction was abolished when cells were pre-incubated with nifedipine, a specific blocker of voltage-gated L-type calcium channels. N-terminal PrP fragments also led to a dose-dependent reduction of the maximal current amplitude, whereas a C-terminal fragment did not affect the current amplitude. These data demonstrate that nanomolar concentrations of PrPC modulate L -type VGCCs in mouse cerebellar granule cells, an effect that is dependent upon the copper-binding amino-terminal domain of PrPC . [ABSTRACT FROM AUTHOR]

Abstract The fundamental physiological function of native cellular prion (PrP[sup C]) remains unknown. Herein, the most salient observations as regards prion physiology are critically evaluated. These include: (i) the role of PrP[sup C] in copper homeostasis, particularly at the pre-synaptic membrane; (ii) involvement of PrP[sup C] in neuronal calcium disturbances; and (iii) the neuroprotective properties of PrP[sup C] in response to copper and oxidative stress. Ultimately, a tentative hypothesis of basic prion function is derived, namely that PrP[sup C] acts as a sensor for copper and/or free radical stimuli, thereby triggering intracellular calcium signals that finally translate into modulation of synaptic transmission and maintenance of neuronal integrity. [ABSTRACT FROM AUTHOR]

1 The intracarotid administration of alkylglycerols has been reported previously by us to be a novel strategy for increased delivery of various chemotherapeutic drugs to the normal brain and brain tumors in rats. 2 Effectiveness and structure-activity relations of the most promising pentyl- and hexylglycerol derivatives have been elucidated in vivo by analyzing the transfer of methotrexate (MTX) across the blood-brain barrier (BBB) in normal rats. The effects were compared with BBB disruption using hypertonic mannitol or intracarotid infusion of bradykinin. Furthermore, toxicity of the alkylglycerols has been studied in long-term experiments. 3 Apart from l-O-pentyldiglycerol, all alkylglycerols induced a concentration-dependent increase in MTX delivery to the brain varying from 1.1 to more than 300-fold compared to intra-arterial MTX alone. Enhanced barrier permeability rapidly approached baseline values within 5 and 120min at the latest. Chemical structure, concentration, time schedule of injections and combination of different alkylglycerols were identified as instruments suited to regulate the MTX accumulation within a wide range. Mannitol 1.4M resulted in very high MTX levels in the brain as observed using the highest concentrations of alkylglycerols. Intracarotid infusion of bradykinin had only a minor effect on the BBB. Using 1-O-pentylglycerol or 2-O-hexyldiglycerol, both cell culture experiments and long-term in vivo analyses including clinical, laboratory and histopathological evaluations revealed no signs of toxicity. 4 In summary, intracarotid short-chain alkylglycerols constitute a very effective and low toxic strategy for transient opening of the BBB to overcome the limited access of cytotoxic drugs to the brain. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have indicated that recombinant cellular prion protein (PrPC), as well as a synthetic peptide of PrPC, affects intracellular calcium homeostasis. To analyze whether calcium homeostasis in neurons is also affected by a loss of PrPC, we performed microfluorometric calcium measurements on cultured cerebellar granule cells derived from prion protein-deficient (Prnp0/0) mice. The resting concentration of intracellular free calcium ([Ca2+]i) was found to be slightly, but significantly, reduced in Prnp0/0 mouse granule cell neurites. Moreover, we observed a highly significant reduction in the [Ca2+]i increase after high potassium depolarization. Pharmacological studies further revealed that the L-type specific blocker nifedipine, which reduces the depolarization-induced [Ca2+]i increase by 66% in wild-type granule cell somas, has no effect on [Ca2+]i in Prnp0/0 mouse granule cells. Patch-clamp measurements, however, did not reveal a reduced calcium influx through voltage-gated calcium channels in Prnp0/0 mice. These data clearly indicate that loss of PrPC alters the intracellular calcium homeostasis of cultured cerebellar granule cells. There is no evidence, though, that this change is due to a direct alteration of voltage-gated calcium channels. [ABSTRACT FROM AUTHOR]

Background: The novel PSEN1single amino acid deletion mutation F175del causes autosomal dominant Alzheimer disease (ADAD) in the late thirties. In vitroF175del features an unusual pattern of APP fragments including an increased production of Aβ39. This Aβ species was found particularly in brain vessels and therefore may contribute to the development of cerebral amyloid angiopathy (CAA). Method: Neuropathological examination was performed in a patient with ADAD caused by PSEN1F175del who died at the age of 45 years. Clinical, neuropsychological, genetic and biomarker findings in this patient as well effects of the PSEN1deletion mutation on Aβ processing were described before (Vöglein et al, Neurobiology of Aging, 2019). Result: Copious cored/compact and diffuse Aβ plaques were found in the cerebral cortex. Interestingly, there were plentiful streaky and several cored/compact and diffuse Aβ plaques also in the cerebellum. A large number of cortical neuropil threads and neurons with fibrillary cytoplasmatic tau aggregates as well as several neuritic plaques were detected (ABC score: A3/B3/C3). CAA with Aβ depositions in the leptomeningeal and cortical vessel walls was detected (Thal phase 2). Furthermore, several Lewy bodies and Lewy neurites were found in the cerebral cortex (Braak stage 6). Conclusion: The neuropathological hallmarks of AD, Aβ plaques and neurofibrillary degeneration, were present in PSEN1 F175del associated ADAD. CAA was found that could be in causal connection with the enhanced Aβ 39 generation caused by the mutation as shown in cell culture. Further, an unusually high cerebellar Aβ burden was detected. In summary, we provide neuropathological characteristics of ADAD caused by PSEN1 F175del and potentially unveiled an effect of an altered Aβ processing that was shown in vitro on brain pathology. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease, BACE1 protease initiates the amyloidogenic processing of amyloid precursor protein (APP) that eventually results in synthesis of β‐amyloid (Aβ) peptide. Aβ deposition in turn causes accumulation of BACE1 in plaque‐associated dystrophic neurites, thereby potentiating progressive Aβ 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 Aβ‐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 Aβ 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. Synopsis: Tau deletion reduces overt accumulation of BACE1 associated with progressive Aβ deposition. Tau‐targeted therapy emerges as an alternative strategy to normalize BACE1 expression and thus avoid systemic inhibition of physiological BACE activity. Tau deletion alleviates overt accumulation of BACE1 and APP around plaques.Tau deletion reduces plaque‐associated axonal pathology.Tau deletion attenuates plaque formation.Tau deletion reduces plaque compactness. [ABSTRACT FROM AUTHOR]

An obituary for neuroscientist Hans A. Kretzschmar, chair of Neuropathology and director of the Centre for Neuropathology and Prion diseases at the Ludwig Maximilian University Munich in Germany, is presented.