Tau-related Pathology Research Articles

Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (Aβ) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of APH1B, with tau-related pathology. Second, a relation between APOE and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of APOE with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, α-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between TPCN1 (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of ANK3. We found association between BIN1 (rs6733839) and α-synuclein pathology, and replicated a prior association between USP6NL (rs7912495) and Lewy body pathology. Additionally, we also found that UMAD1 (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.

A glycan biomarker predicts cognitive decline in amyloid- and tau-negative patients

Abstract Early detection of Alzheimer’s disease is vital for timely treatment. Existing biomarkers for Alzheimer’s disease reflect amyloid- and tau-related pathology, but it is unknown whether the disease can be detected before cerebral amyloidosis is observed. N-glycosylation has been suggested as an upstream regulator of both amyloid and tau pathology, and levels of the N-glycan structure bisecting N-acetylglucosamine (GlcNAc) correlate with tau in blood and CSF already at preclinical stages of the disease. Therefore, we aimed to evaluate if bisecting GlcNAc could predict future cognitive decline in patients from a memory clinic cohort, stratified by amyloid/tau status. We included 251 patients (mean age: 65.6 ± 10.6 years, 60.6% female) in the GEDOC cohort, from the Memory Clinic at Karolinska University Hospital, Stockholm, Sweden. Patients were classified as amyloid/tau positive or negative based on CSF biomarkers. Cognitive decline, measured by longitudinal Mini-Mental State Examination scores, was followed for an average of 10.7 ± 4.1 years, and modelled using non-linear mixed effects models. Additionally, bisecting N-acetylglucosamine levels were measured in hippocampus and cortex with lectin-based immunohistochemistry in ten Alzheimer’s disease and control brains. We found that CSF bisecting GlcNAc levels were elevated in tau positive individuals compared to tau negative individuals, but not in amyloid positive individuals compared to amyloid negative individuals. In the whole sample, high levels of CSF bisecting GlcNAc predicted earlier cognitive decline. Strikingly, amyloid/tau stratification showed that high CSF bisecting GlcNAc levels predicted earlier cognitive decline in amyloid negative patients (β = 2.53 ± 0.85 years, p = 0.003) and tau negative patients (β = 2.43 ± 1.01 years, p = 0.017), but not in amyloid- or tau-positive patients. Finally, histochemical analysis of bisecting GlcNAc showed increased levels in neurons in hippocampus and cortex of Alzheimer’s disease compared to control brain (fold change = 1.44–1.49, p < 0.001). In conclusion, high CSF levels of bisecting GlcNAc reflected neuronal pathology and predicted cognitive decline in amyloid- and tau-negative individuals, suggesting that abnormal glycosylation precedes cerebral amyloidosis and tau hyperphosphorylation in Alzheimer’s disease. Bisecting N-acetylglucosamine is a promising novel early biomarker for Alzheimer’s disease.

Troriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in 3xTg-AD mice.

Alzheimer's disease (AD) is a neurodegenerative condition in which clinical symptoms are highly correlated with the loss of glutamatergic synapses. While later stages of AD are associated with markedly decreased glutamate levels due to neuronal loss, in the early stages, pathological accumulation of glutamate and hyperactivity contribute to AD pathology and cognitive dysfunction. There is increasing awareness that presynaptic dysfunction, particularly synaptic vesicle (SV) alterations, play a key role in mediating this early-stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta-amyloid (Aβ) and tau-related pathology would exhibit similar presynaptic changes as previously observed in amyloid or tau models separately. Hippocampal cultures from 3xTg mice were used to determine whether presynaptic vesicular glutamate transporters (VGlut) and glutamate are increased at the synaptic level while controlling for postsynaptic activity. We observed that 3xTg hippocampal cultures exhibited increased VGlut1 associated with an increase in glutamate release, similar to prior observations in cultures from tau mouse models. However, the SV pool size was also increased in 3xTg cultures, an effect not previously observed in tau mouse models but observed in Aβ models, suggesting the changes in pool size may be due to Aβ and not tau. Second, we sought to determine whether treatment with troriluzole, a novel 3rd generation tripeptide prodrug of the glutamate modulator riluzole, could reduce VGlut1 and glutamate release to restore cognitive deficits in 8-month-old 3xTg mice. Treatment with troriluzole reduced VGlut1 expression, decreased basal and evoked glutamate release, and restored cognitive deficits in 3xTg mice. Together, these findings suggest presynaptic alterations are early events in AD that represent potential targets for therapeutic intervention, and these results support the promise of glutamate-modulating drugs such as troriluzole in Alzheimer's disease.

Cellular and pathological functions of tau.

Tau protein is involved in various cellular processes, including having a canonical role in binding and stabilization of microtubules in neurons. Tauopathies are neurodegenerative diseases marked by the abnormal accumulation of tau protein aggregates in neurons, as seen, for example, in conditions such as frontotemporal dementia and Alzheimer disease. Mutations in tau coding regions or that disrupt tau mRNA splicing, tau post-translational modifications and cellular stress factors (such as oxidative stress and inflammation) increase the tendency of tau to aggregate and interfere with its clearance. Pathological tau is strongly implicated in the progression of neurodegenerative diseases, and the propagation of tau aggregates is associated with disease severity. Recent technological advancements, including cryo-electron microscopy and disease models derived from human induced pluripotent stem cells, have increased our understanding of tau-related pathology in neurodegenerative conditions. Substantial progress has been made in deciphering tau aggregate structures and the molecular mechanisms that underlie protein aggregation and toxicity. In this Review, we discuss recent insights into the diverse cellular functions of tau and the pathology of tau inclusions and explore the potential for therapeutic interventions.

Pick's Disease Presenting as Tremulous Parkinsonism with Limited Levodopa Response-A Rare Cause of Corticobasal Syndrome.

Corticobasal syndrome is a clinical diagnosis and common pathological causes are corticobasal degeneration, progressive supranuclear palsy and Alzheimer's disease. We would like to highlight a rare but important differential of corticobasal syndrome. A 78-year-old female had a 4-year history of predominantly right-hand rest tremor, worsening of handwriting but no change in cognition. The clinical examination showed right upper limb postural and kinetic tremor, mild wrist rigidity and reduced amplitude of right-sided finger tapping. She was initially diagnosed as idiopathic Parkinson's disease. Five years after onset of symptoms, she demonstrated bilateral myoclonic jerks and right upper limb dystonic posturing. She could not copy movements with the right hand. The magnetic resonance imaging (MRI) revealed disproportionate atrophy in the parietal lobes bilaterally. The clinical diagnosis was changed to probable corticobasal syndrome. She passed away 11 years from onset of symptoms at the age of 85 years. She underwent a post-mortem. The anterior and posterior frontal cortex, anterior cingulate, temporal neocortex, hippocampus and amygdaloid complex demonstrated considerable tau-related pathology consisting of a dense background of neuropil threads, and rounded, paranuclear neuronal inclusions consistent with Pick bodies. The immunostaining for three microtubule binding domain repeats (3R) tau performed on sections from the frontal and temporal lobes, basal ganglia and midbrain highlighted several inclusions whilst no 4R tau was observed. She was finally diagnosed with Pick's disease. Pick's disease can rarely present with clinical features of corticobasal syndrome.

Evidence of mutant huntingtin and tau-related pathology within neuronal grafts in Huntington’s disease cases

A number of post-mortem studies conducted in transplanted Huntington’s disease (HD) patients from various trials have reported the presence of pathological and misfolded proteins, in particular mutant huntingtin (mHtt) and phosphorylated tau neuropil threads, in the healthy grafted tissue. Here, we extended these observations with histological analysis of post-mortem tissue from three additional HD patients who had received similar striatal allografts from the fetal tissue transplantation trial conducted in Los Angeles in 1998. Immunohistochemical staining was performed using anti-mHtt antibodies, EM48 and MW7, as well as anti-hyperphosphorylated tau antibodies, AT8 and CP13. Immunofluorescence was used to assess the colocalization of EM48+ mHtt aggregates with the neuronal marker MAP2 and/or the extracellular matrix protein phosphacan in both the host and grafts. We confirmed the presence of mHtt aggregates within grafts of all three cases as well as tau neuropil threads in the grafts of two of the three transplanted HD patients. Phosphorylated tau was also variably expressed in the host cerebral cortex of all three subjects. While mHtt inclusions were present within neurons (immunofluorescence co-localization of MAP2 and EM48) as well as within the extracellular matrix of the host (immunofluorescence co-localization of phosphacan and EM48), their localization was limited to the extracellular matrix in the grafted tissue. This study corroborates previous findings that both mHtt and tau pathology can be found in the host and grafts of HD patients years post-grafting.

ANU-ADRI scores, tau pathology, and cognition in non-demented adults: the CABLE study

BackgroundIt has been reported that the risk of Alzheimer’s disease (AD) could be predicted by the Australian National University Alzheimer Disease Risk Index (ANU-ADRI) scores. However, among non-demented Chinese adults, the correlations of ANU-ADRI scores with cerebrospinal fluid (CSF) core biomarkers and cognition remain unclear.MethodsIndividuals from the Chinese Alzheimer’s Biomarker and LifestyLE (CABLE) study were grouped into three groups (low/intermediate/high risk groups) based on their ANU-ADRI scores. The multiple linear regression models were conducted to investigate the correlations of ANU-ADRI scores with several biomarkers of AD pathology. Mediation model and structural equation model (SEM) were conducted to investigate the mediators of the correlation between ANU-ADRI scores and cognition.ResultsA total of 1078 non-demented elders were included in our study, with a mean age of 62.58 (standard deviation [SD] 10.06) years as well as a female proportion of 44.16% (n = 476). ANU-ADRI scores were found to be significantly related with MMSE (β = -0.264, P < 0.001) and MoCA (β = -0.393, P < 0.001), as well as CSF t-tau (β = 0.236, P < 0.001), p-tau (β = 0.183, P < 0.001), and t-tau/Aβ42 (β = 0.094, P = 0.005). Mediation analyses indicated that the relationships of ANU-ADRI scores with cognitive scores were mediated by CSF t-tau or p-tau (mediating proportions ranging from 4.45% to 10.50%). SEM did not reveal that ANU-ADRI scores affected cognition by tau-related pathology and level of CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2).ConclusionANU-ADRI scores were associated with cognition and tau pathology. We also revealed a potential pathological mechanism underlying the impact of ANU-ADRI scores on cognition.

Recent insights from non-mammalian models of brain injuries: an emerging literature.

Traumatic brain injury (TBI) is a major global health concern and is increasingly recognized as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Repetitive TBIs (rTBIs), commonly observed in contact sports, military service, and intimate partner violence (IPV), pose a significant risk for long-term sequelae. To study the long-term consequences of TBI and rTBI, researchers have typically used mammalian models to recapitulate brain injury and neurodegenerative phenotypes. However, there are several limitations to these models, including: (1) lengthy observation periods, (2) high cost, (3) difficult genetic manipulations, and (4) ethical concerns regarding prolonged and repeated injury of a large number of mammals. Aquatic vertebrate model organisms, including Petromyzon marinus (sea lampreys), zebrafish (Danio rerio), and invertebrates, Caenorhabditis elegans (C. elegans), and Drosophila melanogaster (Drosophila), are emerging as valuable tools for investigating the mechanisms of rTBI and tauopathy. These non-mammalian models offer unique advantages, including genetic tractability, simpler nervous systems, cost-effectiveness, and quick discovery-based approaches and high-throughput screens for therapeutics, which facilitate the study of rTBI-induced neurodegeneration and tau-related pathology. Here, we explore the use of non-vertebrate and aquatic vertebrate models to study TBI and neurodegeneration. Drosophila, in particular, provides an opportunity to explore the longitudinal effects of mild rTBI and its impact on endogenous tau, thereby offering valuable insights into the complex interplay between rTBI, tauopathy, and neurodegeneration. These models provide a platform for mechanistic studies and therapeutic interventions, ultimately advancing our understanding of the long-term consequences associated with rTBI and potential avenues for intervention.

Fragmentation of functional resting state brain networks in a transgenic mouse model of tau pathology: A metabolic connectivity study using [18F]FDG-PET

In a previous study, regional reductions in cerebral glucose metabolism have been demonstrated in the tauopathy mouse model rTg4510 (Endepols et al., 2022). Notably, glucose hypometabolism was present in some brain regions without co-localized synaptic degeneration measured with [18F]UCB-H. We hypothesized that in those regions hypometabolism may reflect reduced functional connectivity rather than synaptic damage. To test this hypothesis, we performed seed-based metabolic connectivity analyses using [18F]FDG-PET data in this mouse model. Eight rTg4510 mice at the age of seven months and 8 non-transgenic littermates were injected intraperitoneally with 11.1 ± 0.8 MBq [18F]FDG and spent a 35-min uptake period awake in single cages. Subsequently, they were anesthetized and measured in a small animal PET scanner for 30 min. Three seed-based connectivity analyses were performed per group. Seeds were selected for apparent mismatch between [18F]FDG and [18F]UCB-H. A seed was placed either in the medial orbitofrontal cortex, dorsal hippocampus or dorsal thalamus, and correlated with all other voxels of the brain across animals. In the control group, the emerging correlative pattern was strongly overlapping for all three seed locations, indicating a uniform fronto-thalamo-hippocampal resting state network. In contrast, rTg4510 mice showed three distinct networks with minimal overlap. Frontal and thalamic networks were greatly diminished. The hippocampus, however, formed a new network with the whole parietal cortex. We conclude that resting-state functional networks are fragmented in the brain of rTg4510 mice. Thus, hypometabolism can be explained by reduced functional connectivity of brain areas devoid of tau-related pathology, such as the thalamus.

New Insights into Alzheimer's Disease: Novel Pathogenesis, Drug Target and Delivery.

Alzheimer's disease (AD), the most common type of dementia, is characterized by senile plaques composed of amyloid β protein (Aβ) and neurofilament tangles derived from the hyperphosphorylation of tau protein. However, the developed medicines targeting Aβ and tau have not obtained ideal clinical efficacy, which raises a challenge to the hypothesis that AD is Aβ cascade-induced. A critical problem of AD pathogenesis is which endogenous factor induces Aβ aggregation and tau phosphorylation. Recently, age-associated endogenous formaldehyde has been suggested to be a direct trigger for Aβ- and tau-related pathology. Another key issue is whether or not AD drugs are successfully delivered to the damaged neurons. Both the blood-brain barrier (BBB) and extracellular space (ECS) are the barriers for drug delivery. Unexpectedly, Aβ-related SP deposition in ECS slows down or stops interstitial fluid drainage in AD, which is the direct reason for drug delivery failure. Here, we propose a new pathogenesis and perspectives on the direction of AD drug development and drug delivery: (1) aging-related formaldehyde is a direct trigger for Aβ assembly and tau hyperphosphorylation, and the new target for AD therapy is formaldehyde; (2) nano-packaging and physical therapy may be the promising strategy for increasing BBB permeability and accelerating interstitial fluid drainage.

Tryptophan-tyrosine dipeptide improves tau-related symptoms in tauopathy mice

ABSTRACT Neurodegenerative diseases involving pathological tau protein aggregation are collectively known as tauopathies and include Alzheimer’s disease and Pick’s disease. Recent studies show that the intake of tryptophan-tyrosine (Trp-Tyr)-related β-lactopeptides, including β-lactolin, attenuates cognitive decline in the elderly and prevents the amyloid pathology in mouse models of Alzheimer’s disease. However, the effects of Trp-Tyr-related β-lactopeptides on tau-related pathology have not been investigated. In the present study, we examined the effects of Trp-Tyr dipeptide intake on tauopathy in PS19 transgenic mice, a well-established tauopathy model. Intake of Trp-Tyr dipeptide improved the behavioral deficits observed in the open field test, prevented tau phosphorylation, and increased the dopamine turnover and synaptophysin expression in the frontal cortex. Levels of short-chain fatty acids in the cecum were lower in PS19 mice than those in wild-type mice and were increased by treatment with Trp-Tyr dipeptide. In addition, intake of Trp-Tyr dipeptide extended the lifespan of PS19 mice. These findings suggest that the intake of Trp-Tyr-related peptides improves tauopathy symptoms, resulting in improvements in behavioral deficits and longevity. Hence, the intake of Trp-Tyr-related peptides, including β-lactolin, may be beneficial for preventing dementia.

Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women.

Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4-). To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 ε4- women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred. We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, P=4.9×10-8) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P=1.9×10-14) datasets. Multi-omics analyses showed that the most significant and largest number of associations among the single nucleotide polymorphisms (SNPs), DNA-methylated CpGs, MGMT expression, and AD-related neuropathological traits were observed among women. Furthermore, promoter capture Hi-C analyses revealed long-range interactions of the MGMT promoter with MGMT SNPs and CpG sites. These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.

Melatonin ameliorates tau-related pathology via the miR-504-3p and CDK5 axis in Alzheimer’s disease

BackgroundIntracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer’s disease (AD). Melatonin has been shown to prevent tau hyperphosphorylation in cellular and animal models. However, the molecular mechanisms by which melatonin attenuates tau hyperphosphorylation and tau-related pathologies are not fully understood.MethodsImmunofluorescence, immunoblotting analysis and thioflavin-S staining were employed to examine the effects of early and late treatment of melatonin on tau-related pathology in hTau mice, in which nonmutated human tau is overexpressed on a mouse tau knockout background. High-throughput microRNA (miRNA) sequencing, quantitative RT-PCR, luciferase reporter assay and immunoblotting analysis were performed to determine the molecular mechanism.ResultsWe found that both early and late treatment of melatonin efficiently decreased the phosphorylation of soluble and insoluble tau at sites related to AD. Moreover, melatonin significantly reduced the number of neurofibrillary tangles (NFTs) and attenuated neuronal loss in the cortex and hippocampus. Furthermore, using miRNA microarray analysis, we found that miR-504-3p expression was upregulated by melatonin in the hTau mice. The administration of miR-504-3p mimics dramatically decreased tau phosphorylation by targeting p39, an activator of the well-known tau kinase cyclin-dependent kinase 5 (CDK5). Compared with miR-504-3p mimics alone, co-treatment with miR-504-3p mimics and p39 failed to reduce tau hyperphosphorylation.ConclusionsOur results suggest for the first time that melatonin alleviates tau-related pathologies through upregulation of miR-504-3p expression by targeting the p39/CDK5 axis and provide novel insights into AD treatment strategies.

Assessment of the In Vivo Relationship Between Cerebral Hypometabolism, Tau Deposition, TSPO Expression, and Synaptic Density in a Tauopathy Mouse Model: a Multi-tracer PET Study

Cerebral glucose hypometabolism is a typical hallmark of Alzheimer’s disease (AD), usually associated with ongoing neurodegeneration and neuronal dysfunction. However, underlying pathological processes are not fully understood and reproducibility in animal models is not well established. The aim of the present study was to investigate the regional interrelation of glucose hypometabolism measured by [18F]FDG positron emission tomography (PET) with various molecular targets of AD pathophysiology using the PET tracers [18F]PI-2620 for tau deposition, [18F]DPA-714 for TSPO expression associated with neuroinflammation, and [18F]UCB-H for synaptic density in a transgenic tauopathy mouse model. Seven-month-old rTg4510 mice (n = 8) and non-transgenic littermates (n = 8) were examined in a small animal PET scanner with the tracers listed above. Hypometabolism was observed throughout the forebrain of rTg4510 mice. Tau pathology, increased TSPO expression, and synaptic loss were co-localized in the cortex and hippocampus and correlated with hypometabolism. In the thalamus, however, hypometabolism occurred in the absence of tau-related pathology. Thus, cerebral hypometabolism was associated with two regionally distinct forms of molecular pathology: (1) characteristic neuropathology of the Alzheimer-type including synaptic degeneration and neuroinflammation co-localized with tau deposition in the cerebral cortex, and (2) pathological changes in the thalamus in the absence of other markers of AD pathophysiology, possibly reflecting downstream or remote adaptive processes which may affect functional connectivity. Our study demonstrates the feasibility of a multitracer approach to explore complex interactions of distinct AD-pathomechanisms in vivo in a small animal model. The observations demonstrate that multiple, spatially heterogeneous pathomechanisms can contribute to hypometabolism observed in AD mouse models and they motivate future longitudinal studies as well as the investigation of possibly comparable pathomechanisms in human patients.

Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study

SummaryBackgroundTherapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease.MethodsWe did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models.FindingsIn carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=–4·28 × 10–2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=–5·51 × 10–3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=–0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020).InterpretationOur findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing.FundingGerman Research Foundation, US National Institutes of Health.

Hsp90 co-chaperone degradation combined with antioxidation nanostrategy to rescue tauopathy-induced Alzheimer’s disease

• HMPB-AAG nanoagent enhances Hsp40/Hsp70-mediated p-tau degradation. • HMPB-AAG nanoagent inhibits oxidative stress and neuroinflammation. • HMPB-AAG nanoagent ameliorates tauopathy-induced synaptic damage and apoptosis. • This nanoagent is promising for rescuing tauopathy-induced Alzheimer’s disease. Tau pathology is a major hallmark and potential drug therapeutic target of Alzheimer’s disease (AD). Effective clearance of hyperphosphorylated tau protein (p-tau) is very difficult, not only because the intracellular repair defense collapses and degradation fails, but also because the extracellular pathological environment always aggravates its production. Herein, hollow mesoporous prussian blue nanoparticles (HMPB NPs) loaded with a high-affinity Hsp90 inhibitor 17-AAG are constructed as HMPB-AAG nanoagents for the combined rescue of tauopathy-induced AD. In this nanoagent, 17-AAG achieves Hsp90 co-chaperone degradation of p-tau and HMPB NPs exert antioxidation property. In vitro and in vivo studies reveal that HMPB-AAG nanoagents can produce a combinational therapeutic effect on tau-related pathology by reducing p-tau levels, alleviating oxidative stress and neuroinflammation, and inhibiting neuronal apoptosis and synaptic damage. Hippocampal stereotaxic microinjections of HMPB-AAG nanoagents into okadaic acid-induced AD-like rats have shown to significantly reverse tauopathy-induced cognitive impairment. Overall, this work takes advantage of the combination of intracellular and extracellular regulatory strategies targeting tau hyperphosphorylation, providing a promising and efficient therapeutic candidate agent for AD and other tau-related neurodegenerative diseases.

Progranulin mutations in clinical and neuropathological Alzheimer's disease.

Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology. We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers. Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort. GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with β-amyloid load or AD.

Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer disease among women.

Increasing evidence suggests epidemiological and pathological links between Alzheimer disease (AD) and breast cancer (BC). The 17q21 locus, including MAPT encoding tau, has been identified in genome-wide association studies (GWAS) for BC in women and AD among persons lacking the APOE ε4 allele (ε4-). We hypothesized that other genes involved in tau-related pathology can be identified by GWAS in women stratified by ε4 status. We conducted a GWAS for AD among ε4- women (3,400 AD and 6,940 controls) in Alzheimer's Disease Genetics Consortium (ADGC) datasets and separately analyzed whole genome sequencing data obtained from five AD cases (all women; ε4+=4) and 26 controls (17 women, 9 men; ε4+=9) in a Hutterite kindred from South Dakota. Association tests were performed using logistic regression with covariates for age and principle components of ancestry in the ADGC datasets and for age, sex, and ε4 in the Hutterites. Potential mechanisms of top-ranked findings were investigated by integrating omics data including gene expression, DNA-methylation (DNAm), and AD-related neuropathological traits in subsets stratified by sex and ε4 status in the Religious Orders Study and Memory and Aging Project (ROSMAP; 339 AD and 229 controls). We identified genome-wide significant associations with one novel locus MGMT in each sample (ADGC: rs12775171, odds ratio [OR]=1.4, P=4.9x10-8 ; Hutterites: rs12256016, OR=2.0, P=1.9x10-14 ). Rs12775171 showed no evidence of association with AD risk in ε4+ women or in men in the ADGC datasets (P>0.05). Rs12775171 is not in linkage disequilibrium with rs12256016. At least one of these SNPs was significantly associated with increased DNAm levels near/within MGMT (best association pair: rs11016864 [proxy for rs12256016] with cg01419164; P=4.0x10-4 in women), which were also significantly associated with lower MGMT expression (P=0.03) and worse tau burden in all AD cohorts (neurofibrillary tangle; P=6.0x10-3 ), women (Braak stage; P=4.0x10-3 ), and ε4- women (neurofibrillary tangle; P=0.03), but not among ε4+ women, all men, or ε4+/ε4- men in ROSMAP. We identified a novel association of AD with the interaction of sex and MGMT. Our omics analysis confirmed that epigenetically regulated expression of MGMT (involved in DNA methylation damage repair) is significantly associated with tau in women.

P-tau and neurodegeneration mediate the effect of \u03b2-amyloid on cognition in non-demented elders

BackgroundThere are many pathological changes in the brains of Alzheimer’s disease (AD) patients. For many years, the mainstream view on the pathogenesis of AD believes that β-amyloid (Aβ) usually acts independently in addition to triggering functions. However, the evidence now accumulating indicates another case that these pathological types have synergies. The objective of this study was to investigate whether effects of Aβ pathology on cognition were mediated by AD pathologies, including tau-related pathology (p-tau), neurodegeneration (t-tau, MRI measurements), axonal injury (NFL), synaptic dysfunction (neurogranin), and neuroinflammation (sTREM2, YKL-40).MethodsThree hundred seventy normal controls (CN) and 623 MCI patients from the ADNI (Alzheimer’s Disease Neuroimaging Initiative) database were recruited in this research. Linear mixed-effects models were used to evaluate the associations of baseline Aβ with cognitive decline and biomarkers of several pathophysiological pathways. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of AD pathologies on cognition.ResultsTau-related pathology, neurodegeneration, neuroinflammation are correlated with the concentration of Aβ, even in CN participants. The results show that age, gender, and APOE ε4 carrier status have a moderating influence on some of these relationships. There is a stronger association of Aβ with biomarkers and cognitive changes in the elderly and females. In CN group, Aβ pathology is directly related to poor cognition and has no mediating effect (p < 0.05). In mild cognitive impairment, tau-related pathology (26.15% of total effect) and neurodegeneration (14.8% to 47.0% of total effect) mediate the impact of Aβ on cognition.ConclusionsIn conclusion, early Aβ accumulation has an independent effect on cognitive decline in CN and a tau, neurodegeneration-dependent effect in the subsequent cognitive decline in MCI patients.

Amelioration of tau related pathology with a novel anti‐prion protein monoclonal antibody in an AD mouse model

AbstractBackgroundA number of studies have shown that amyloid β oligomers (Aβo) mediate their toxicity, in part, via the cellular prion protein (PrPC) on the surface of neurons. We hypothesized that tau oligomers may also mediate toxicity and spread of pathology via PrPC. We have generated a novel monoclonal anti‐PrP antibody (TW1) and assessed the efficacy of passive immunization with this antibody in a mouse model of AD with only tau related pathology.MethodHTau/PS1 transgenic AD model mice were injected at 5 months of age intraperitoneally once a week with TW1 from the age of 5 months. Control mice received only saline. Their behavior was assessed at 8 months of age and brain tissue subsequently harvested for analysis at 9 monthsResultThe treated and control mice did not show any significant differences in sensorimotor testing. Significant statistical differences were observed with the novel object recognition test in the immunized mice on percentage time spent in zones (two tailed, t‐test p = 0.0019). On the closed field symmetrical maze immunized mice performed significantly better (Day1: two tailed t‐test p=0.0001; Day2: two tailed t‐test p=0.0015; Day3: two tailed t‐test p=0.0002). Fifty percent less tau pathology was observed in the dentate gyrus with PHF‐1 immunolabeling (two tailed t‐test p= 0.02) and a 60% reduction was seen in the piriform cortex (two‐tailed, t‐test p=0.01) in treated vs control animals. CP13 immunolabeling showed a significant difference in the piriform cortex (p=0.02, two‐tailed t‐test) in treated mice versus controls. There was no significant difference in astrogliosis or microgliosis in treated versus control mice. Western blots using PHF‐1 showed that TW1 therapy reduced phosphorylated tau pathology (two‐tailed t‐test p=0.03) and improved the ratio of pathological soluble tau to tubulin (two‐tailed t‐test p=0.0006). The same effect were observed with the CP13 antibody (two‐tailed t‐test p=0.0007) and improved the ratio CP13/tubulin (two tailed, t‐test p=0.0014).ConclusionThese results indicate that passive immunization with the TW1 antibody can significantly decrease tau pathology and improve cognition in a transgenic mouse model of AD.