Increased Tau Pathology Research Articles

A - 14 Sleep and Tauopathies: a Review

Abstract Objective This project highlights a narrative review investigating the relation between sleep and tauopathies (a disease which reflects the pathological changes in the brain’s tau protein). Tauopathies are often associated with aging disorders and causes of dementia, including Alzheimer’s disease. Sleep is a behavioral modifiable risk factor that has been implicated in many of these disorders, but the process, relationship, and mechanisms remain largely unknown. Understanding relationships between behaviors and disease pathology is crucial to furthering our understanding of causes of disorders, as there are no known cures for neurodegenerative tauopathies. Data Selection This review was registered with Prospero, a database of potential systematic reviews, and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. The search took place between August and November 2023. Databases included PubMed, APA PsycInfo, MEDLINE, and Cochrane Library. Key words included “sleep,” “tau,” and “dementia.” Study requirements included a measure of sleep and tau, and a human sample that had been diagnosed with a tauopathy. Data Synthesis The search yielded 319 unique results. A three-person team independently reviewed titles for relativity and inclusion first, then reviewed abstracts to determine eligibility. A total of 22 papers were found to meet review criteria. Conclusion A majority of studies (n = 21) found correlations between impaired sleep and increased tau pathology. A subset analysis that reviewed studies with neuropsychological testing (n = 6) found increased cognitive impairment with poorer sleep and increased tau pathology. There is a continued need for longitudinal studies to understand the impacts of lifestyle behaviors on pathology development.

Innate Immune Activation in Mouse Models of Amyloidosis and Tauopathy

For many years scientists have felt that innate immune activation in the brain (some call this inflammation) played a role in Alzheimer's dementia, and may provide a useful drug target. This hypothesis has been reinforced by the genetic studies which identified many innate immune gene variants that modulate the risk of developing Alzheimer's. Our initial studies testing the hypothesis examined immune activation in models of amyloidosis using lipopolysaccharide and vaccination. Surprisingly, both led to reduced amyloidosis. Additional studies regulated immune activation using gene therapy in both models of amyloidosis and tauopathy. In many instances, an intervention that benefited amyloidosis was found to exacerbate tauopathy and vice versa. In studies of innate immune markers in human CSF, there are some biomarkers that are lower in individuals who are amyloid positive compared to those without amyloid, but which increase in cases with both amyloid and tau positivity. Although the results regarding central nervous system innate immune activation are sometimes discordant with respect to amyloid or tau pathology, recent data find that systemic immune activation by serial exposures to PAMPs, results in both increased tau pathology and increased amyloid pathology. In conclusion, innate immune activation can have differential effects on amyloidosis or tauopathy and the effects of central and systemic inflammation may also be different. Specific targeting of select aspects of innate immunity will be necessary at different stages of the disease to moderate the progression of Alzheimer's disease.

INPP5D is associated with tau seeding and tau pathogenesis

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia characterized by extracellular amyloid deposits and intracellular neurofibrillary tangles composed of hyperphosphorylated tau aggregates. GWAS studies have identified variants in several inflammatory genes as significant risk factors for AD, highlighting that neuroinflammation is a critical, underlying pathological component in AD. INPP5D, a family member of Src homology 2 domain containing inositol 5' polyphosphatases (SHIPs), is an AD risk gene related to innate immunity in late‐onset AD (LOAD). Inpp5d plays a role in regulating signal transduction initiated by immune cell surface receptors. INPP5D binds receptor ITIMs, competes with kinases, and converts PI(3,4,5)P3 to PI(3,4)P¬2, thereby limiting downstream signaling. We previously reported that Inpp5d expression is increased in LOAD and is positively correlated with amyloid burden. However, the relationship of Inpp5d in tau pathology remains unclear. We hypothesize that inhibiting INPP5D will release the break and increase microglial function.MethodsTo assess the role of Inpp5d in tau pathology, we performed a fluorescence resonance energy transfer (FRET) assay on human‐AD brains obtained from NCRAD. We also crossed a mouse model deficient in Inpp5d (Inpp5d+/−) with a PS19 model of tau pathology and measured tau phosphorylation and transcriptomics. Primary microglia were utilized to measure microglial internalization of Tau.ResultsIn human AD‐ brains, increased tau seeding was positively correlated with Inpp5d expression. Furthermore, in PS19 mice, Inpp5d protein expression was upregulated and positively correlated with phosphorylated tau (S202, Thr205). Utilizing the NanoString nCounter assay, we found an upregulation of the immune‐related and cell migration related genes in PS19.Inpp5d+/‐ mice compared to PS19 mice. Primary microglia from Inpp5d+/− mice released increased tau internalization compared to WT microglia.ConclusionOur findings confirmed that elevated Inpp5d expression in human‐AD subjects is recapitulated in PS19 mice and correlated with increased tau pathology. In PS19.Inpp5d+/‐ mice we found alterations in immune related and cell migration related pathways suggesting that Inpp5d modulates the disease progression through these pathways. Furthermore, pathogenesis may be modulated through increased internalization of tau. Together these results suggest that therapeutic interventions aimed at reducing Inpp5d may be beneficial in tauopathies.

Understanding molecular and cellular mechanisms of APOE4‐mediated susceptibility to tau‐related cognitive impairments in the miBrain model

AbstractBackgroundAPOE4 is the strongest genetic risk factor for Alzheimer’s disease with Tau pathology, namely hyperphosphorylation (p‐Tau) and aggregation of Tau into neurofibrillary tangles (NFTs) being correlated with poor cognitive outcomes in AD. Instances of mild traumatic brain injury (TBI) have been associated with increased susceptibility to neurodegenerative diseases such as AD and related dementias. We hypothesize that human APOE4 carriers’ brains are more susceptible to increased tau pathology with instances of TBI further increasing the severity.MethodUsing the 3D multi‐cellular integrated human brain (miBrain) model, which recapitulates key brain tissues through the co‐culturing of all hiPSC‐derived major brain cell‐types, Tau pathology can be induced with treatment of Tau fibrils or by increasing endogenous phosphorylated Tau with methotrexate.ResultAPOE4/4 miBrain cultures exhibit increased Tau pathology compared to isogenic APOE3/3 miBrains. Combinatorial genetic mixing experiments revealed that the increase of Tau hyperphosphorylation is dependent on the presence of APOE4 microglia.ConclusionData suggests that microglia facilitate the accumulation of p‐tau in APOE4 genetic backgrounds in an in vitro 3D model.

TREM2 as an evolving therapeutic target in Alzheimer's disease.

TREM2 as an evolving therapeutic target in Alzheimer's disease.

Morphological differences between the two major subtypes of multiple system atrophy with cognitive impairment

ObjectiveTo compare the neuropathology between two types of multiple system atrophy - parkinsonism-predominant (MSA-P) and cerebellar ataxia-predominant (MSA-C) with cognitive impairment. Material & methods35 cases of MSA-P (mean age at death 60.5 ± 7.8 years) and 15 cases of MSA-C (mean age at death 61.3 ± 6.8 years), 35.% of which associated with mild to moderate cognitive impairment and one with severe dementia, were examined neuropathologically with semiquantitative evaluation of both α-synuclein and Alzheimer pathologies, including cerebral amyloid angiopathy (CAA) and other co-pathologies. ResultsWhile the mean age at death of both MSA subgroups was similar, the age at onset and duration of disease were slightly higher in the MSA-C group. In line with the classification, the αSyn pathology glial and neuronal inclusions in both the cortex and brainstem were significantly higher in the MSA-P group. With regard to the Alzheimer disease pathology, tau load in cases with mild to moderate cognitive impairment was slightly but not significantly higher in the MSA-P group, one with severe dementia showing fully developed Alzheimer co-pathology, while the amyloid-β (Aβ) load including the CAA was higher in the MSA-C group. The presence of Lewy co-pathology in this series (20%), being similar to that of other MSA cohorts, was more frequent in MSA cases with mild to severe cognitive impairment, but did not differ between the two subgroups and seems not essentially important for MCI in MSA. ConclusionsIn agreement with previous clinical studies that reported more severe cognitive dysfunction in patients with MSA-P, the present neuropathological study showed increased tau pathology in MSA-P and one with severe Alzheimer co-pathology, but only slightly increased amyloid pathology in the MSA-C group. Lewy co-pathology was more frequent in MSA-P cases with cognitive decline. In view of the limited data about the pathobiological basis of cognitive impairment in MSA, further studies to elucidate the differences between the two phenotypes are urgently needed.

Cerebral amyloid angiopathy interacts with parenchymal beta‐amyloid to promote tau and cognitive decline

AbstractBackgroundPrior work has shown that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and progression toward AD dementia. Cerebral amyloid angiopathy (CAA) is a form of cerebrovascular pathology that results from the buildup of β‐amyloid (Aβ) in the vessel walls. CAA commonly co‐occurs with AD pathology and increases the risk of AD dementia. Here, we examined whether CAA influences tau deposition and cognitive decline, independently or synergistically with parenchymal Aβ burden. Secondarily, we examined whether tau burden mediates the association between CAA and cognitive decline.MethodWe included data from autopsied subjects recruited from one of three longitudinal clinical‐pathological cohort studies at Rush University. Participants completed annual cognitive evaluations and underwent brain autopsy. CAA pathology was rated as none, mild, moderate, or severe. We used linear regression and linear mixed models to test independent versus interactive effects of CAA and neuritic plaques on tau burden and cognitive decline. We used causal mediation models to examine whether tau mediates the association between CAA and cognitive decline at low and high neuritic plaque burden.ResultWe included 1722 autopsied subjects (mean age at baseline = 80.2+7.1; mean age at death = 8.9+6.7; 68% women). CAA interacted with neuritic plaques to promote tau burden and cognitive decline, such that those with more severe CAA and higher neuritic plaque burden exhibited greater tau and faster cognitive decline (Figures 1 and 2). Tau mediated the effect of CAA on cognitive decline among participants with high neuritic plaque burden. Specifically, increased tau pathology due to the presence of severe CAA led to a 5‐year decline in cognition that was 0.10 (95% CI: 0.03 ‐ 0.19) SD units greater than those with no CAA. A direct effect of CAA on cognitive decline (i.e., an effect not mediated by tau) was not significant in the low or high neuritic plaque groups (Figure 3).ConclusionThese results highlight the dynamic interplay between cerebrovascular and AD pathways in the progression of AD. The present findings have implications for AD clinical trials and therapeutic development, and further support the idea that improving and/or preserving the brain’s vasculature might be an effective target for AD prevention

APOE Alleles With Tau and Aβ Pathology in Patients With Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex in the Kii Peninsula.

To examine the association of the APOE ε4 and ε2 alleles with the pathologic features of patients with amyotrophic lateral sclerosis and parkinsonism-dementia complex cases in the Kii peninsula of Japan (Kii ALS/PDC). We analyzed APOE variants in 18 autopsy patients with ALS/PDC, consisting of 9, 8, and 1 patient with PDC, ALS, and PDC followed by ALS, respectively. Moreover, we revealed the relationship between APOE variants and Aβ and tau pathologies. The frequency of the ε4 allele was not different between patients with Kii ALS/PDC and control participants. APOE ε4 was associated with increased Aβ pathology (p = 0.005 by the χ 2 test), but not with increased tau pathology (p = 0.984). The frequency of the ε2 allele was apparently higher than that of control participants (p = 0.254). The APOE ε2 allele was associated with increased tau pathology (p = 0.009) and not with reduced Aβ pathology (p = 0.383) in patients with Kii ALS/PDC. Although there was no overrepresentation of the frequency of the ε4 or ε2 allele, our findings suggest that the ε2 allele is associated with increased tau pathology and not with reduced Aβ pathology in patients with Kii ALS/PDC.

Association between lower body temperature and increased tau pathology in cognitively normal older adults

BackgroundPreclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. MethodsTb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. ResultsLower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). ConclusionsThese results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. Clinical trial number: NCT03053908.

Wolframin is a novel regulator of tau pathology and neurodegeneration.

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD.

Astrocytic α2-Na+/K+ ATPase inhibition suppresses astrocyte reactivity and reduces neurodegeneration in a tauopathy mouse model.

Alzheimer's disease (AD) is the most dominant form of dementia characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tau tangles (NFTs). In addition to these pathologies, an emerging pathophysiological mechanism that influences AD is neuroinflammation. Astrocytes are a vital type of glial cell that contribute to neuroinflammation, and reactive astrocytes, or astrogliosis, are a well-known pathological feature of AD. However, the mechanisms by which astrocytes contribute to the neurodegenerative process in AD have not been fully elucidated. Here, we showed that astrocytic α2-Na+/K+ adenosine triphosphatase (α2-NKA) is elevated in postmortem human brain tissue from AD and progressive nuclear palsy, a primary tauopathy. The increased astrocytic α2-NKA was also recapitulated in a mouse model of tauopathy. Pharmacological inhibition of α2-NKA robustly suppressed neuroinflammation and reduced brain atrophy. In addition, α2-NKA knockdown in tauopathy mice halted the accumulation of tau pathology. We also demonstrated that α2-NKA promoted tauopathy, in part, by regulating the proinflammatory protein lipocalin-2 (Lcn2). Overexpression of Lcn2 in tauopathy mice increased tau pathology, and prolonged Lcn2 exposure to primary neurons promoted tau uptake in vitro. These studies collectively highlight the contribution of reactive astrocytes to tau pathogenesis in mice and define α2-NKA as a major regulator of astrocytic-dependent neuroinflammation.

Associations between cognition, Aβ, and tau in adults with Down syndrome

AbstractBackgroundAdults with Down syndrome (DS) are widely affected by AD pathology by their 30’s and have a 70‐80% chance of clinical dementia by their 60’s. The aim of the present study was to explore the relationship between cognitive decline and tau pathology using a regression model to explore the associations between longitudinal rates of cognition and the cross‐sectional tau burden in adults with DS.MethodNinety‐two participants (age=39.19±8.44 at time of tau scan) with DS with multiple cognitive assessments over a period of 9 years, PiB scans over a period of 8 years, and one [18F]AV‐1451 scan were analyzed. Cognitive assessments included tests of overall function (DSMSE), memory (cued recall), executive function (Stroop), and motor function (Purdue pegboard). FreeSurfer (v5.3.0) was used for the definition of ROIs. A two‐stage analysis was performed for cognition and AV‐1451 correlations or PiB and AV‐1451 correlations: 1) a linear mixed model was applied to estimate the rates of change for cognitive outcomes or PiB over time and 2) the cognitive or PiB estimated rates from the trajectories were used as predictors of interest in a correlation analysis with AV‐1451 for each Braak‐associated (1‐6) region as the outcome.ResultStatistically significant associations were found between AV‐1451 retention in all Braak regions and cognitive assessments at alpha=0.05 , including cued recall, DSMSE, and the Purdue pegboard task, but not for the Stroop test (Table 1). Statistically significant associations were also found in Braak regions 3‐6 at alpha=0.05 between longitudinal PiB estimated amyloid trajectories and cross‐sectional AV‐1451 retention.ConclusionFor this DS population, we found inverse associations between rates of neuropsychological decline and higher tau pathology. In particular, decline in global cognition, verbal memory and motor function were all associated with higher tau pathology, while executive function was not. Further, longitudinal analyses demonstrated an association between cross‐sectional and accumulating amyloid pathology with increased tau pathology in regions associated with higher Braak stages.

Sex-Related Motor Deficits in the Tau-P301L Mouse Model.

The contribution of mouse models for basic and translational research at different levels is important to understand neurodegenerative diseases, including tauopathies, by studying the alterations in the corresponding mouse models in detail. Moreover, several studies demonstrated that pathological as well as behavioral changes are influenced by the sex. For this purpose, we performed an in-depth characterization of the behavioral alterations in the transgenic Tau-P301L mouse model. Sex-matched wild type and homozygous Tau-P301L mice were tested in a battery of behavioral tests at different ages. Tau-P301L male mice showed olfactory and motor deficits as well as increased Tau pathology, which was not observed in Tau-P301L female mice. Both Tau-P301L male and female mice had phenotypic alterations in the SHIRPA test battery and cognitive deficits in the novel object recognition test. This study demonstrated that Tau-P301L mice have phenotypic alterations, which are in line with the histological changes and with a sex-dependent performance in those tests. Summarized, the Tau-P301L mouse model shows phenotypic alterations due to the presence of neurofibrillary tangles in the brain.

Medial temporal lobe connectivity and its associations with cognition in early Alzheimer's disease.

Human episodic memory critically depends on subregions of the medial temporal lobe, which are part of functional brain systems such as the anterior-temporal and the posterior-medial system. Here we analysed how Alzheimer's pathology affects functional connectivity within these systems. Data from 256 amyloid-β-negative cognitively unimpaired, 103 amyloid-β-positive cognitively unimpaired, and 83 amyloid-β-positive individuals with mild cognitive impairment were analysed. Amyloid-β and tau pathology were measured using the CSF amyloid-β42/40 ratio and phosphorylated tau, respectively. We found that amyloid-β-positive cognitively unimpaired individuals were mainly characterized by decreased functional connectivity between the medial temporal lobe and regions in the anterior-temporal system, most prominently between left perirhinal/entorhinal cortices and medial prefrontal cortex. Furthermore, correlation analysis in this group revealed decreasing functional connectivity between bilateral perirhinal/entorhinal cortices, anterior hippocampus and posterior-medial regions with increasing levels of phosphorylated tau. The amyloid-β-positive individuals with mild cognitive impairment mostly exhibited reduced connectivity between the medial temporal lobe and posterior-medial regions, predominantly between the anterior hippocampus and posterior cingulate cortex. In addition, they showed hyperconnectivity within the medial temporal lobe and its immediate proximity. Lower medial temporal-cortical functional connectivity networks resulting from the group comparisons of cognitively unimpaired individuals were associated with reduced memory performance and more rapid longitudinal memory decline as shown by linear mixed-effects regression analysis. Finally, we found that reduced medial temporal-cortical connectivity in mildly cognitively impaired individuals was related to reduced entorhinal thickness and white matter integrity of the parahippocampal cingulum and the fornix. No such relationships were found in cognitively unimpaired individuals. In conclusion, our findings show that the earliest changes in preclinical Alzheimer's disease might involve decreased connectivity within the anterior-temporal system, and early changes in connectivity might be related to memory impairment, but not to structural changes. With disease progression and increased tau pathology, medial temporal functional connectivity with posterior-medial regions seems to be increasingly impaired. In individuals with mild cognitive impairment, reduced functional connectivity is associated with structural brain changes as well as the emergence of locally increased connectivity patterns. Thus, functional connectivity between the medial temporal lobe and the anterior-temporal and posterior-medial system could serve as stage-specific functional markers in early Alzheimer's disease.

Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E \u03b54 genotype

Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) ε4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE ε4, we examined the dorsolateral frontal cortex from deceased participants within a community-based aging cohort (n = 154). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology only in APOE ε4 positive participants (p = 0.001). The cytokines IL-10, IL-13, IL-4, and IL-1α were negatively associated with tau pathology, independent of Aβ1–42 levels, only in APOE ε4 negative participants. Overall, the association of mostly anti-inflammatory cytokines with less tau pathology suggests a protective effect in APOE ε4 negative participants. These associations are largely absent in the presence of APOE ε4 where tau pathology was significantly associated with increased microglial cell density. Taken together, these results suggest that APOE ε4 mediates an altered inflammatory response and increased tau pathology independent of Aβ1–42 pathology.

THE APOE-ε4 ALLELE AND AGE SYNERGISTICALLY DRIVE DISEASE PROGRESSION IN ALZHEIMER’S DISEASE

The Apolipoprotein E (APOE)-ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD) and other neurodegenerative dementias. Cross-sectional case-control studies suggest that the effect of APOE-ε4 decreases in old age. However, since APOE- ε4 is associated with mortality, these studies might be prone to bias due to selective survival. Therefore, we used multi-state-modeling in longitudinal cohort studies to examine the effect of APOE-ε4 on the transition through cognitive states (i.e. cognitively normal, mild cognitive impairment (MCI) and dementia) while taking death as a competing risk into account. Results from the German AgeCoDe study (n=3000, aged 75-101 years) showed that APOE-ε4 increases the risk for cognitive deterioration in all disease stages. Contrary to results from cross-sectional studies, the effect of APOE-ε4 on the transition from MCI to dementia increased with increasing age (HR=1.044, 95%-CI=1.001-1090). The direction of this effect was confirmed in a smaller sample from the Einstein Aging Study (n=744, HR=1.032, 95%-CI=0.949-1.122). To examine the pathophysiological basis of these results, generalized additive models were used to study AD biomarkers in the liquor of 1045 patients with MCI or AD-dementia. Here, increased amyloid (Abeta1-42) pathology was associated with increased tau pathology (pTau181), consistent with the amyloid-cascade-hypothesis. Interestingly, higher age and presence of the APOE-ε4 synergistically lowered the amount of amyloid required to exacerbate tau pathology (interaction p=0.012). Taken together, our results suggest that the effect of APOE-ε4 on disease progression increases with advancing age. An altered neuroinflammatory response to neurodegeneration should be further explored as potential underlying mechanism.

Synergistic toxicity in an in vivo model of neurodegeneration through the co-expression of human TDP-43M337V and tauT175D protein

Although it has been suggested that the co-expression of multiple pathological proteins associated with neurodegeneration may act synergistically to induce more widespread neuropathology, experimental evidence of this is sparse. We have previously shown that the expression of Thr175Asp-tau (tauT175D) using somatic gene transfer with a stereotaxically-injected recombinant adeno-associated virus (rAAV9) vector induces tau pathology in rat hippocampus. In this study, we have examined whether the co-expression of human tauT175D with mutant human TDP-43 (TDP-43M337V) will act synergistically. Transgenic female Sprague-Dawley rats that inducibly express mutant human TDP-43M337V using the choline acetyltransferase (ChAT) tetracycline response element (TRE) driver with activity modulating tetracycline-controlled transactivator (tTA) were utilized in these studies. Adult rats were injected with GFP-tagged tau protein constructs in a rAAV9 vector through bilateral stereotaxic injection into the hippocampus. Injected tau constructs were: wild-type GFP-tagged 2N4R human tau (tauWT; n = 8), GFP-tagged tauT175D 2N4R human tau (tauT175D, pseudophosphorylated, toxic variant, n = 8), and GFP (control, n = 8). Six months post-injection, mutant TDP-43M337V expression was induced for 30 days. Behaviour testing identified motor deficits within 3 weeks after TDP-43 expression irrespective of tau expression, though social behaviour and sensorimotor gating remained unchanged. Increased tau pathology was observed in the hippocampus of both tauWT and tauT175D expressing rats and tauT175D pathology was increased in the presence of cholinergic neuronal expression of human TDP-43M337V. These data indicate that co-expression of pathological TDP-43 and tau protein exacerbate the pathology associated with either individual protein.

The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory

The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer’s disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II–VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology.

The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans.

The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

A single systemic inflammatory insult causes acute motor deficits and accelerates disease progression in a mouse model of human tauopathy

IntroductionNeuroinflammation, which contributes to neurodegeneration, is a consistent hallmark of dementia. Emerging evidence suggests that systemic inflammation also contributes to disease progression. MethodsThe ability of systemically administered lipopolysaccharide (LPS - 500 μg/kg) to effect acute and chronic behavioural changes in C57BL/6 and P301S tauopathy mice was assessed. Markers of pathology were assessed in the brain and spinal cord. ResultsP301S mice display regional microgliosis. Systemic LPS treatment induced exaggerated acute sickness behaviour and motor dysfunction in P301S mice compared with wild-type controls and advanced the onset and accelerated chronic decline. LPS treatment was associated with increased tau pathology 24 hours after LPS injection and spinal cord microgliosis at the end stage. DiscussionThis is the first demonstration that a single systemic inflammatory episode causes exaggerated acute functional impairments and accelerates the long-term trajectory of functional decline associated with neurodegeneration in a mouse model of human tauopathy. The findings have relevance to management of human dementias.