Presence Of Tau Pathology Research Articles

Synaptic dysfunction, Tau pathology and Neurodegeneration

AbstractBackgroundTau plays a prominent role in the synapse and has been shown to be closely related to neurodegeneration. Recent evidence show that cerebrospinal fluid (CSF) synaptic markers are related to CSF tau and degeneration. However, it is not clear whether synaptic dysfunction in combination with tau tangles is associated with neurodegeneration in the same brain regions. Our study aims to map in the brain the association of synaptic markers with tau and degeneration.MethodWe evaluated 147 individuals from the TRIAD cohort with CSF GAP43, SYT1, SNAP25, neurogranin (Ng), ptau217, neurofilament light protein (NfL) quantification, as well as tau positron emission tomography (PET), magnetic resonance imaging, and clinical assessments. One‐way ANOVA tested group differences on synaptic levels. Spearman correlation tested the association among synaptic proteins. Linear regressions tested the association between biomarkers. Voxel‐based morphometry (VBM) was considered as an index of neurodegeneration.ResultWe observed an increase in synaptic markers across age and the AD spectrum, reaching a plateau when cognition is affected (Figure 1A). Among the synaptic markers, SNAP25 showed the greatest magnitude of change, on average, between young, aged cognitively unimpaired, mild cognitive impaired, and AD individuals (mean 62.44%). (Figure 1B‐C). In addition, we found that all synaptic markers are significantly intercorrelated (Figure 1D). Moreover, CSF ptau217 correlated with all synaptic biomarkers, GAP43 (β = ‐044), SYT1 (β = ‐0.41), SNAP25 (β = ‐0.59) and Ng (β = ‐0.25). Conversely, CSF NfL was strongly but only correlated with GAP43 (β = 0.62) (Figure 2). Voxel‐wise correlation revealed that tau tangles measured by [18F]‐MK6240 PET, was positively associated with SNAP25 in AD‐related regions, and VBM was associated with all synaptic markers, but more closely with GAP43. Furthermore, the interaction between synaptic markers and temporal meta‐ROI [18F]‐MK6240 on VBM was significant for Ng and GAP43 (Figure 3).ConclusionOur results support a heterogenous role of synaptic markers in the AD continuum and suggest that synaptic dysfunction in the presence of tau pathology may not be driving atrophy.

Effect of early‐ and mid‐life cognitive enrichment on Alzheimer’s disease pathology and late‐life cognition

AbstractBackgroundCognitive reserve and brain maintenance may explain individual differences in trajectories of cognitive and brain aging due to various life exposures (e.g., education, cognitive enrichment). Cognitive reserve refers to the advantages that life exposures exert on cognitive abilities despite brain aging or disease; brain maintenance refers to the protective effects of life exposures on the brain itself (e.g., reduced rate of neuropathology accumulation). Previous findings showed that early‐life cognitive enrichment (ELCE) was associated with slower cognitive decline, which was partially mediated through global Alzheimer’s disease pathology. Building on this work, this study investigated mediation by β‐amyloid and tau pathology (reflecting brain maintenance) as well as moderation by early‐ and mid‐life cognitive enrichment (ELCE, MLCE; reflecting cognitive reserve) on cognitive functioning at last visit proximate to death.MethodThere were 1015 community‐based participants (M baseline age = 82.57±6.35) from the Rush Memory and Aging Project (MAP) and Minority Aging Research Study (MARS) cohorts, who completed annual cognitive and clinical assessments. ELCE and MLCE composite measures were derived from z‐scored self‐reported indicators obtained at baseline (Table 1). Summary measures of β‐amyloid and tau burden were derived from immunohistochemistry at autopsy. Late‐life cognition was measured using a global composite of 19 z‐scored neuropsychological tests obtained at last visit. To test for cognitive reserve, separate linear regression models examined whether ELCE and MLCE moderated relations between β‐amyloid or tau and cognition, adjusted for age at death and sex. To test for brain maintenance, a series of mediation analyses examined whether β‐amyloid and/or tau burden mediated the relationship of ELCE and MLCE with cognition.ResultELCE (p = .005) and MLCE (p = .005) moderated the relationship between tau—but not β‐amyloid—and late‐life cognition proximate to death (Figure 1). Mediation analyses revealed an indirect effect of β‐amyloid—but not tau—on the relation between ELCE (B = 0.058, p = .004) and MLCE (B = 0.040, p = .03) and late‐life cognition (Figure 2).ConclusionELCE and MLCE improve late‐life cognition partially through reducing β‐amyloid, but not tau, accumulation (i.e., brain maintenance). In contrast, ELCE and MLCE are protective against late‐life cognitive impairment in the presence of tau pathology (i.e., cognitive reserve), but not β‐amyloid.

Modulation of cannabinoid receptor‐2 alters brain clearance of human tau

AbstractBackgroundMultiple studies have demonstrated a strong neuroinflammatory response in the presence of Tau pathology, which is strongly associated with the clinical symptoms and cognitive decline found in Alzheimer’s disease (AD). The correlation between AD progression and tau pathologies, rather than Ab accumulation, suggests that targeting pathological tau may be a more effective therapeutic approach. Microglia have been implicated in tauopathies as they may contribute to tau phosphorylation and aggregation and the uptake and spread of seed‐competent tau to healthy neurons due to dysfunctional degradation. Cannabinoid type 2 receptors (CB2) are highly expressed in immune cells and upregulated in activated microglia under conditions of neurologic disease, such as AD. The pharmacological modulation of CB2 have demonstrated a reduction in inflammation and plaque deposition, suggesting a role of CB2 on the immune system to influence AD‐related pathologies and phenotypes. However, there are limited findings on the CB2 regulation of tau accumulation.MethodWe have generated organotypic brain slice cultures from CB2‐EGFP/f/f mice and transduced with rAAV‐P301L/S320F‐human tau, which previously has shown to accumulate total tau and develop insoluble tau species. Slices were treated with CB2‐selective compounds and evaluated for tau pathology and microglial phenotypes using real‐time imaging and biochemical analyses.ResultPrevious investigation in our lab of a synucleinopathy animal model revealed the capacity of CB2 signaling to alter the function of immune cells and reduce accumulation of phosphorylated human alpha‐synuclein. Furthermore, we have determined that treatment with a CB2 inverse agonist will increase phagocytosis of pHrodo E. coli bioparticles in microglia BV2 cultures stimulated by LPS. Our preliminary work in brain slices over‐expressing mutant human tau show a trend toward reduced ratio of phosphorylated tau (Ser202/Thr205) to total tau in the soluble protein fraction (p = 0.0549) in slices treated with CB2 inverse agonist SR144528 compared to vehicle. We are repeating the experiment and performing further evaluations in organotypic brain slice cultures from CB2‐KO mice.ConclusionThese studies will advance our understanding of the role of brain CB2 in pathologic tau removal and potentially highlight CB2 as a therapeutic target against tauopathies such as AD.

Synaptic dysfunction in the presence of tau tangles is not a strong predictor of atrophy

AbstractBackgroundTau plays a prominent role in the synapse and has been shown to be closely related to neurodegeneration. Recent evidence show that cerebrospinal fluid (CSF) synaptic markers are related to CSF tau and degeneration. However, it is not clear whether synaptic dysfunction in combination with tau tangles is associated with neurodegeneration in the same brain regions. Our study aims to map in the brain the association of synaptic markers with tau and degeneration.MethodWe evaluated 147 individuals from the TRIAD cohort with CSF GAP43, SYT1, SNAP25, neurogranin (Ng), ptau217, neurofilament light protein (NfL) quantification, as well as tau positron emission tomography (PET), magnetic resonance imaging, and clinical assessments. One‐way ANOVA tested group differences on synaptic levels. Spearman correlation tested the association among synaptic proteins. Linear regressions tested the association between biomarkers. Voxel‐based morphometry (VBM) was considered as an index of neurodegeneration.ResultWe observed an increase in synaptic markers across age and the AD spectrum, reaching a plateau when cognition is affected (Figure 1A). Among the synaptic markers, SNAP25 showed the greatest magnitude of change, on average, between young, aged cognitively unimpaired, mild cognitive impaired, and AD individuals (mean 62.44%). (Figure 1B‐C). In addition, we found that all synaptic markers are significantly intercorrelated (Figure 1D). Moreover, CSF ptau217 correlated with all synaptic biomarkers, GAP43 (ß = ‐044), SYT1 (ß = ‐0.41), SNAP25 (ß = ‐0.59) and Ng (ß = ‐0.25). Conversely, CSF NfL was strongly but only correlated with GAP43 (ß = 0.62) (Figure 2). Voxel‐wise correlation revealed that tau tangles measured by [18F]‐MK6240 PET, was positively associated with SNAP25 in AD‐related regions, and VBM was associated with all synaptic markers, but more closely with GAP43. Furthermore, the interaction between synaptic markers and temporal meta‐ROI [18F]‐MK6240 on VBM was significant for Ng and GAP43 (Figure 3).ConclusionOur results support a heterogenous role of synaptic markers in the AD continuum and suggest that synaptic dysfunction in the presence of tau pathology may not be driving atrophy.

Post‐mortem assessment of retinal phosphorylated tau and amyloid beta in a cohort of neurodegenerative diseases.

AbstractBackgroundThe retina provides an opportunity for development of a screening tool to detect early stages of AD. Studies showing the presence of Aβ and p‐tau in AD retina are contradictory, and their characterization in a large, neuropathologically confirmed cohort with different neurodegenerative diseases is scarce. In this study we assessed the presence of different tau isoforms and Aβ (4G8) in the retinas of AD cases, control cases, as well as other neurodegenerative diseases, and correlated these directly to cortical cerebral tau and amyloid pathology loads.MethodPost mortem eyes (N = 62) with both clinical history and post‐mortem neuropathological reports available were collected through the Netherlands Brain Bank. Donors included AD, PSP, CBD, FTLD, PD(D), DLB, MSA, ALS, MS and controls, with and without cerebral cortical p‐tau. Superior‐temporal quadrants were cut in 10 µm sections. Sections were immunostained using antibodies directed against p‐tau (AT270, AT100, AT8, pS422) and Aβ (4G8). Linear mixed models were used to analyze between‐group differences and the relation between brain and retina.ResultTau appeared as a diffuse neuritic staining, and in some cases as somatodendritic‐like staining and was mainly present in the plexiform layers of the retina. AT8, AT100 and AT270 immunoreactivity showed a predilection in the far periphery. AT8 was generally found in tauopathy cases as opposed to non‐tauopathy cases. A strong correlation was found between retinal AT8 and brain cortical tau pathology. 4G8 appeared sporadically as extracellular structures, mainly present in the retinal nerve fiber layer, ganglion cell layer and near blood vessels. 4G8 did not differ between control and disease cases, and no group differences or relation with cortical amyloid load was found.ConclusionP‐tau measured with AT8 in the retina correlates with the presence of tau pathology in cortical brain areas. In contrast, Aβ (4G8) immunoreactivity is sporadically present in the retina, is not specific for AD and does not correlate with cortical amyloid load in a large cross‐disease cohort. Our study shows that p‐tau detected in the retina by AT8 is a potential biomarker candidate for tauopathies.

The role of cannabinoid receptor 2 in microglial clearance of human tau.

It is well accepted that neuroinflammation is a key component in the pathobiology of Alzheimer's disease (AD). Multiple studies have demonstrated a strong neuroinflammatory response in the presence of Tau pathology, which is strongly associated with the clinical symptoms and cognitive decline found in AD patients. The correlation between AD progression and tau pathologies, rather than Ab accumulation, suggests that targeting pathological tau may be a more effective therapeutic approach. Microglia have been implicated in tauopathies as they may contribute to tau phosphorylation and aggregation and the uptake and spread of seed-competent tau to healthy neurons due to dysfunctional degradation. Cannabinoid type 2 receptors (CB2) are highly expressed in immune cells and upregulated in activated microglia under conditions of neurologic disease, such as AD. Moreover, the pharmacological modulation of CB2 using CB2-selective compounds have demonstrated a reduction in inflammation and plaque deposition, suggesting a role of CB2 on the immune system to influence AD-related pathologies and phenotypes. However, there are limited findings on the CB2 regulation of tau accumulation. Brain slice cultures will be generated from CB2-EGFP knock-in mice and transduced with virus-mediated tau previously shown to accumulate total tau and develop insoluble tau species. Brain slices will be evaluated for tau pathology and microglial phenotypes using real-time imaging and biochemical analyses. Previous investigation in our lab of a synucleinopathy animal model revealed the capacity of CB2 to alter the function of immune cells and reduce accumulation of toxic human alpha-synuclein. Furthermore, we have determined that treatment with a CB2 inverse agonist will increase phagocytosis of pHrodo E. coli bioparticles in microglia BV2 cultures stimulated by LPS. We are currently working with brain slice cultures to evaluate how CB2 alters the behavior of microglia including phagocytosis and clearance of human tau. These studies will advance our understanding of the role of CB2 in the microglial contribution to pathologic tau removal and potentially highlight CB2 as a therapeutic target against tauopathies such as AD.

Tau pathology reshapes GFAP-positive astrocytes phenotype.

Astrocytes are glial cells widely distributed in the human brain. It is well established that they perform vital functions for proper brain functioning. In pathological conditions, they adapt by changing morphology, function, and overexpressing specific proteins, such as the glial fibrillary acidic protein (GFAP). This phenomenon is called astrocyte reactivity and it is present in Alzheimer's disease (AD). It is now a consensus that reactive astrocytes present multiple phenotypes, which are likely driven by specific pathological agents. In this context, whether tau pathology induces changes in astrocyte phenotypes is not precisely understood. Here, we aimed at evaluating hippocampal astrocyte phenotypes in the presence of tau pathology in a transgenic human tau mouse model. We hypothesize that hippocampal astrocytes will respond to tau pathology by assuming a reactive phenotype. Hippocampal GFAP-positive astrocytes data from 6 month-old PS19 mice (Prnp.Tau.P301S.tg.B6N, n = 6), which harbor the microtubule-associated protein tau human P301S mutation, and wild-type littermates (WT, n = 5) were obtained from GEO (GSE129797) and used to identify differentially expressed genes (DEGs) and changes in biological processes. Initially, raw fastq data reads were submitted to quality control assessments. Then, Salmon algorithm was used on high quality RNAseq samples. DEGs were evaluated using the DESeq2 method. Further data analysis included Gene Ontology (GO) functional evaluation. All analyses were performed using R/Bioconductor. Principal component analyses (PCA) clearly differentiated gene expression from PS19 and WT hippocampi GFAP+ astrocytes (Figure 1A). We identified 1264 up-regulated and 634 down-regulated genes in PS19 astrocytes in comparison to WT mice (Figure 1B-C). Remarkably, neuronal death was the first hit among the top 10 altered GO terms (Figure 1D). We identified a phenotypic gene expression profile in hippocampal astrocytes of mice presenting with tau pathology. Therefore, our findings suggest tau pathology changes astrocyte phenotypes, which may help in advancing our understanding of AD pathophysiology.

Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils.

Alzheimer’s disease and primary tauopathies are characterized by the presence of tau pathology in brain. Several tau positron emission tomography (PET) tracers have been developed and studied in Alzheimer’s disease (AD), but there is still a lack of 4R-tau specific tracers for non-AD tauopathies. We here present the first computational study on the binding profiles of four tau different PET tracers, PI2620, CBD2115, PM-PBB3, and MK6240, to corticobasal degeneration (CBD) tau. The in silico results showed different preferences for the various binding sites on the 4R fibril, and especially an entry site, a concave site, and a core site showed high binding affinity to these tracers. The core site and entry site both showed higher binding affinity than the surface sites, but the tracers were less likely to enter these sites. PI2620, CBD2115, and PM-PBB3 all showed higher binding affinities to CBD tau than the 3R/4R tracer MK6240. The same strategy has also been applied to AD tau fibrils, and significant differences in selectivity of binding sites were also observed. A higher binding affinity was observed for CBD2115 and PM-PBB3 to AD tau compared to PI2620. None of the studied tracers showed a selectivity for 4R compared to 3R/4R tau. This study clearly shows that identified binding sites from cryo-EM with low resolution can be further refined by metadynamics simulations in order to provide atomic resolution of the binding modes as well as of the thermodynamic properties.

Dynamic Amyloid PET: Relationships to 18F-Flortaucipir Tau PET Measures.

Measuring amyloid and predicting tau status using a single amyloid PET study would be valuable for assessing brain AD pathophysiology. We hypothesized that early-frame amyloid PET (efAP) correlates with the presence of tau pathology because the initial regional brain concentrations of radioactivity are determined primarily by blood flow, which is expected to be decreased in the setting of tau pathology. Methods: The study included 120 participants (63 amyloid-positive and 57 amyloid-negative) with dynamic 18F-florbetapir PET and static 18F-flortaucipir PET scans obtained within 6 mo of each other. These subjects were predominantly cognitively intact in both the amyloid-positive (63%) and the amyloid-negative (93%) groups. Parameters for efAP quantification were optimized for stratification of tau PET positivity, assessed by either a tauopathy score or Braak regions. The ability of efAP to stratify tau positivity was measured using receiver-operating-characteristic analysis of area under the curve (AUC). Pearson r and Spearman ρ were used for parametric and nonparametric comparisons between efAP and tau PET, respectively. Standardized net benefit was used to evaluate improvement in using efAP as an additional copredictor over hippocampal volume in predicting tau PET positivity. Results: Measuring efAP within the hippocampus and summing the first 3 min of brain activity after injection showed the strongest discriminative ability to stratify for tau positivity (AUC, 0.67-0.89 across tau PET Braak regions) in amyloid-positive individuals. Hippocampal efAP correlated significantly with a global tau PET tauopathy score in amyloid-positive participants (r = -0.57, P < 0.0001). Compared with hippocampal volume, hippocampal efAP showed a stronger association with tau PET Braak stage (ρ = -0.58 vs. -0.37) and superior stratification of tau PET tauopathy score (AUC, 0.86 vs. 0.66; P = 0.002). Conclusion: Hippocampal efAP can provide additional information to conventional amyloid PET, including estimation of the likelihood of tau positivity in amyloid-positive individuals.

The Role of Mitochondrial Impairment in Alzheimer´s Disease Neurodegeneration: The Tau Connection.

Accumulative evidence has shown that mitochondrial dysfunction plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial impairment actively contributes to the synaptic and cognitive failure that characterizes AD. The presence of soluble pathological forms of tau like hyperphosphorylated at Ser396 and Ser404 and cleaved at Asp421 by caspase 3, negatively impacts mitochondrial bioenergetics, transport, and morphology in neurons. These adverse effects against mitochondria health will contribute to the synaptic impairment and cognitive decline in AD. Current studies suggest that mitochondrial failure induced by pathological tau forms is likely the result of the opening of the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial mega-channel that is activated by increases in calcium and is associated with mitochondrial stress and apoptosis. This structure is composed of different proteins, where Ciclophilin D (CypD) is considered to be the primary mediator of mPTP activation. Also, new studies suggest that mPTP contributes to Aβ pathology and oxidative stress in AD.Further, inhibition of mPTP through the reduction of CypD expression prevents cognitive and synaptic impairment in AD mouse models. More importantly, tau protein contributes to the physiological regulation of mitochondria through the opening/interaction with mPTP in hippocampal neurons. Therefore, in this paper, we will discuss evidence that suggests an important role of pathological forms of tau against mitochondrial health. Also, we will discuss the possible role of mPTP in the mitochondrial impairment produced by the presence of tau pathology and its impact on synaptic function present in AD.

Presence of tau pathology within foetal neural allografts in patients with Huntington's and Parkinson's disease.

Cell replacement has been explored as a therapeutic strategy to repair the brain in patients with Huntington's and Parkinson's disease. Post-mortem evaluations of healthy grafted tissue in such cases have revealed the development of Huntington- or Parkinson-like pathology including mutant huntingtin aggregates and Lewy bodies. An outstanding question remains if tau pathology can also be seen in patients with Huntington's and Parkinson's disease who had received foetal neural allografts. This was addressed by immunohistochemical/immunofluorescent stainings performed on grafted tissue of two Huntington's disease patients, who came to autopsy 9 and 12 years post-transplantation, and two patients with Parkinson's disease who came to autopsy 18 months and 16 years post-transplantation. We show that grafts also contain tau pathology in both types of transplanted patients. In two patients with Huntington's disease, the grafted tissue showed the presence of hyperphosphorylated tau [both AT8 (phospho-tau Ser202 and Thr205) and CP13 (pSer202) immunohistochemical stainings] pathological inclusions, neurofibrillary tangles and neuropil threads. In patients with Parkinson's disease, the grafted tissue was characterized by hyperphosphorylated tau (AT8; immunofluorescent staining) pathological inclusions, neurofibrillary tangles and neuropil threads but only in the patient who came to autopsy 16 years post-transplantation. Abundant tau-related pathology was observed in the cortex and striatum of all cases studied. While the striatum of the grafted Huntington's disease patient revealed an equal amount of 3-repeat and 4-repeat isoforms of tau, the grafted tissue showed elevated 4-repeat isoforms by western blot. This suggests that transplants may have acquired tau pathology from the host brain, although another possibility is that this was due to acceleration of ageing. This finding not only adds to the recent reports that tau pathology is a feature of these neurodegenerative diseases, but also that tau pathology can manifest in healthy neural tissue transplanted into the brains of patients with two distinct neurodegenerative disorders.

Threonine175, a novel pathological phosphorylation site on tau protein linked to multiple tauopathies

Microtubule associated protein tau (tau) deposition is associated with a spectrum of neurodegenerative diseases collectively termed tauopathies. We have previously shown that amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) is associated with tau phosphorylation at Thr175 and that this leads to activation of GSK3β which then induces phosphorylation at tau Thr231. This latter step leads to dissociation of tau from microtubules and pathological tau fibril formation. To determine the extent to which this pathway is unique to ALS, we have investigated the expression of pThr175 tau and pThr231 tau across a range of frontotemporal degenerations. Representative sections from the superior frontal cortex, anterior cingulate cortex (ACC), amygdala, hippocampal formation, basal ganglia, and substantia nigra were selected from neuropathologically confirmed cases of Alzheimer’s disease (AD; n = 3), vascular dementia (n = 2), frontotemporal lobar degeneration (FTLD; n = 4), ALS (n = 5), ALSci (n = 6), Parkinson’s disease (PD; n = 5), corticobasal degeneration (CBD; n = 2), diffuse Lewy body dementia (DLBD; n = 2), mixed DLBD (n = 3), multisystem atrophy (MSA; n = 6) and Pick’s disease (n = 1) and three neuropathologically-normal control groups aged 50–60 (n = 6), 60–70 (n = 6) and 70–80 (n = 8). Sections were examined using a panel of phospho-tau antibodies (pSer208,210, pThr217, pThr175, pThr231, pSer202 and T22 (oligomeric tau)). Across diseases, phospho-tau load was most prominent in layers II/III of the entorhinal cortex, amygdala and hippocampus. This is in contrast to the preferential deposition of phospho-tau in the ACC and frontal cortex in ALSci. Controls showed pThr175 tau expression only in the 7th decade of life and only in the presence of tau pathology and tau oligomers. With the exception of DLBD, we observed pThr175 co-localizing with pThr231 in the same cell populations as T22 positivity. This suggests that this pathway may be a common mechanism of toxicity across the tauopathies.

3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice.

3D volume imaging using iDISCO+ was applied to observe the spatial and temporal progression of tau pathology in deep structures of the brain of a mouse model that recapitulates the earliest stages of Alzheimer’s disease (AD). Tau pathology was compared at four timepoints, up to 34 months as it spread through the hippocampal formation and out into the neocortex along an anatomically connected route. Tau pathology was associated with significant gliosis. No evidence for uptake and accumulation of tau by glia was observed. Neuronal cells did appear to have internalized tau, including in extrahippocampal areas as a small proportion of cells that had accumulated human tau protein did not express detectible levels of human tau mRNA. At the oldest timepoint, mature tau pathology in the entorhinal cortex (EC) was associated with significant cell loss. As in human AD, mature tau pathology in the EC and the presence of tau pathology in the neocortex correlated with cognitive impairment. 3D volume imaging is an ideal technique to easily monitor the spread of pathology over time in models of disease progression.

Mitochondrial Dysfunction Contributes to the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease that affects millions of people worldwide. Currently, there is no effective treatment for AD, which indicates the necessity to understand the pathogenic mechanism of this disorder. Extracellular aggregates of amyloid precursor protein (APP), called Aβ peptide and neurofibrillary tangles (NFTs), formed by tau protein in the hyperphosphorylated form are considered the hallmarks of AD. Accumulative evidence suggests that tau pathology and Aβ affect neuronal cells compromising energy supply, antioxidant response, and synaptic activity. In this context, it has been showed that mitochondrial function could be affected by the presence of tau pathology and Aβ in AD. Mitochondria are essential for brain cells function and the improvement of mitochondrial activity contributes to preventing neurodegeneration. Several reports have suggested that mitochondria could be affected in terms of morphology, bioenergetics, and transport in AD. These defects affect mitochondrial health, which later will contribute to the pathogenesis of AD. In this review, we will discuss evidence that supports the importance of mitochondrial injury in the pathogenesis of AD and how studying these mechanisms could lead us to suggest new targets for diagnostic and therapeutic intervention against neurodegeneration.

Are cases with tau pathology occurring in the absence of Aβ deposits part of the AD-related pathological process?

and only at the same predilection sites as the tau lesions that are present in individuals with Aβ and in fully developed AD can represent possible preclinical (early) stages of the AD-related pathological process. In other words, an interim or transient absence of a minimum of Aβ deposits is not an adequate or compelling rationale for excluding tau-only cases from the developmental spectrum of the ADrelated process, nor is the existence of such cases in nonaged individuals (compare Table 3 here with Table 1 in [8]) consistent with the term ‘primary age-related tauopathy.’ The authors claim that PART, in contrast to AD, is probably not APOE e4 allele-driven. However, an earlier study showing that non-demented individuals with NFT stage I pathology displayed a significantly higher APOE e4 allele frequency than controls [11] reached the opposite conclusion. That study was retrospective (cross sectional), but so were the studies in the supporting literature (13, 67, 70, 122, 150, 151) cited by Crary et al. [8], who have not incorporated into their thinking the implications of recent original findings showing that neuronal injury develops independently of Aβ in APOE e4 allele carriers [7, 13]. The fundamental question whether 3R + 4R tau-only cases and cases with 3R + 4R tau plus Aβ deposits belong to essentially different pathological processes cannot be resolved without identifying potentially unique mechanisms for cases with tau-only pathology, e.g., by means of experimental models of tau seeding and neuron-to-neuron transmission [12], in which tau extracts are isolated not from AD brains but from brains of individuals with autopsy-confirmed 3R + 4R tau-only lesions. Biomarkerbased research and positron emission tomography (PET) imaging of brain Aβ and of tau that can quantify abnormalities in AD-associated neurodegeneration [19] have the developmental potential to reach the point at which the presence and progression of both pathological proteins can The current neuropathological diagnosis of clinically suspected Alzheimer’s disease (AD) requires the presence of advanced neurofibrillary tangle (NFT) stages and of Aβ deposits in the brain [15]. Both abnormal proteins (intraneuronal forms of aggregated and hyperphosphorylated tau and extracellular Aβ) develop at different times at different predilection sites and progress gradually but inexorably during the pathological process by sequential spreading into previously uninvolved regions. Tau pathology develops prior to Aβ deposits [1, 5, 6]. In their position paper, Crary et al. [8] present arguments for distinguishing two processes: an ‘AD-related process’ and a non-AD-related ‘primary age-related tauopathy’ (PART). Both are characterized by the presence of 3R and 4R tau isoforms as well as paired helical filaments but they differ in that the first displays the combined presence of tau and Aβ pathologies, whereas the second is marked by the presence of tau pathology alone. Nevertheless, application of the criteria required to confirm neuropathologically that the diagnosis of clinically manifest AD [15] does not warrant the disqualification of tau-only cases because the statement that “a diagnosis of AD neuropathologic changes requires at least a minimum threshold level of Aβ deposition” [8] is correct only in cases with clinically diagnosed AD but is inaccurate when applied to non-demented individuals. In the absence of Aβ deposits, tau pathology consisting of 3R and 4R isoforms that occurs in the same neuronal cell types as those known to be vulnerable to the pathological process underlying AD

Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice.

BackgroundAmyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer’s disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology.ResultsWe treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques.ConclusionsThis study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.

Alterations of neurotrophin signaling in the retina of the P301S mutant human tau transgenic mouse

been reported in degenerative diseases of the retina. For instance, altered levels of tau protein have been detected in the retina and optic nerve of patients with glaucoma, suggesting that retina and brain degeneration share similar pathogenic mechanisms. We have recently demonstrated that P301S mutant human tau mice (tau P301S) develop tau filamentous inclusions and axonopathy in retinal ganglion neurons (RGCs), in the absence of neuronal loss and that transgenic retinal explants do not respond to neurotrophic stimuli in vitro. Methods:We investigated the impact of tau pathology on BDNF signaling pathway in RGC of adult wild type (WT) and tau P301S mice. Protein and mRNA expression of neurotrophins and their receptors was investigated by western blot and quantitative RT-PCR analyses in retina extracts of WT and tau P301S mice. The activation of the BDNF signaling pathway in vivo was evaluated under basal conditions and upon stimulation with the ligand. Results: Protein levels of BDNF and TrkB receptor were significantly altered in the retina of 5-month old tau P301S mice. The change was not due to altered expression and protein synthesis as the levels of mRNA and pro-BDNF were similar in WT and transgenic retinas. The activation of TrkB signaling was evaluated using antibodies directed towards specific phospho-tyrosine residues. Altered activation state was detected both in basal and BDNF-stimulated retinas of tau P301S mice. Conclusions: These data indicate that the presence of tau pathology is associated with alteration of neurotrophin signaling in the retina of tau P301S mice.

β-Amyloid triggers ALS-associated TDP-43 pathology in AD models

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with loss of motor neurons in the brain and spinal cord. ALS is occasionally diagnosed with frontotemporal lobar dementia with ubiquitin-positive inclusions (FTLD-U). Alzheimer's disease (AD) is the most common type of age-associated dementia. Abnormal levels of aggregated Tar-DNA binding protein-43 (TDP-43) are detected in the majority of patients with ALS, FTLD and AD. We observed a significant increase (200%) in the levels of TDP-43 in cortical autopsies of late stage AD patients. Lentiviral expression of Aβ 1–42 in the rat motor cortex led to an increase in TDP-43 pathology, including up-regulation of the mature ~ 44 kDa protein, identical to the pathological changes seen in AD. Furthermore, expression of Aβ 1–42 was associated with TDP-43 phosphorylation and accumulation in the cytosol. Clearance of Aβ with parkin prevented TDP-43 pathology. TDP-43 modifications were also observed in 3xTransgenic AD (3xTg-AD) compared to wild type mice, but these changes were attenuated in parkin-injected hippocampi, even in the presence of Tau pathology, suggesting that TDP-43 pathology is triggered by Aβ, independent of Tau. Increased levels of casein kinase (CK1 and CK2), which are associated with TDP-43 phosphorylation, were also observed in Aβ 1–42 expressing brains. These data indicate an overlap in TDP-43 pathology between AD and ALS-FTLD and suggest that Aβ triggers modifications of TDP-43.

Familial prion disease with a novel serine to isoleucine mutation at codon 132 of prion protein gene (PRNP)

Familial prion disease with a novel serine to isoleucine mutation at codon 132 of prion protein gene (<i>PRNP</i>)

The Tauopathies: Toward an Experimental Animal Model

Abundant intraneuronal neurofibrillary lesions within certain brain regions constitute a defining neuropathological characteristic of Alzheimer’s disease. 1 Ultrastructurally, the neurofibrillary lesions consist of abnormal filamentous deposits in the form of paired helical filaments (PHFs) and the related straight filaments (SFs). These filaments are made of the microtubule-associated protein tau in a hyperphosphorylated state. In normal brain, tau protein is soluble and nonfilamentous. Its ordered assembly into filaments is therefore a pathological event. Tau pathology is not limited to Alzheimer’s disease but is also present in a number of other dementing disorders, such as Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. 2,3 In these disorders, as in Alzheimer’s disease, the hyperphosphorylated tau protein is filamentous. However, the filament morphologies and tau isoform compositions differ from those of Alzheimer’s disease. The good correlation between the presence of tau pathology and the degree of cognitive impairment has suggested that the events leading to the formation of tau filaments or the mere presence of these filaments are sufficient to produce nerve cell degeneration. Recently, this view has been significantly reinforced by the discovery of mutations in the tau gene in familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). 4-8 The new work will no doubt lead to increased efforts aimed at producing experimental animal models of the tau pathology of Alzheimer’s disease and other tauopathies.