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Background: Tau hyperphosphorylation at several sites, including those close to its microtubule domain (MD), is considered a key pathogenic event in the development of tauopathies. Nevertheless, we recently demonstrated that at the very early disease stage, tau phosphorylation (pTau) at MD sites promotes neuroprotection by preventing seizure-like activity. Objective: To further support the notion that very early pTau is not detrimental, the present work evaluated the young rTg4510 mouse model of tauopathy as a case study. Thus, in mice at one month of age (PN30-35), we studied the increase of pTau within the hippocampal area as well as hippocampal and locomotor function. Methods: We used immunohistochemistry, T-maze, nesting test, novel object recognition test, open field arena, and electrophysiology. Results: Our results showed that the very young rTg4510 mouse model has no detectable changes in hippocampal dependent tasks, such as spontaneous alternation and nesting, or in locomotor activity. However, at this very early stage the hippocampal neurons from PN30-35 rTg4510 mice accumulate pTau protein and exhibit changes in hippocampal oscillatory activity. Moreover, we found a significant reduction in the somatic area of pTau positive pyramidal and granule neurons in the young rTg4510 mice. Despite this, improved memory and increased number of dendrites per cell in granule neurons was found. Conclusion: Altogether, this study provides new insights into the early pathogenesis of tauopathies and provides further evidence that pTau remodels hippocampal function and morphology.

For more than five decades, the field of Alzheimer’s disease (AD) has focused on two main hypotheses positing amyloid-beta (Aβ) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.

Transgenic mice have been used to make valuable contributions to the field of neuroscience and model neurological diseases. The simultaneous functional analysis of hippocampal cell activity combined with hippocampal dependent innate task evaluations provides a reliable experimental approach to detect fine changes during early phases of neurodegeneration. To this aim, we used a merge of patch-clamp with two hippocampal innate behavior tasks. With this experimental approach, whole-cell recordings of CA1 pyramidal cells, combined with hippocampal-dependent innate behaviors, have been crucial for evaluating the early mechanism of neurodegeneration and its consequences. Here, we present our protocol for ex vivo whole-cell recordings of CA1 pyramidal cells and hippocampal dependent innate behaviors in an adolescent (p30) mice.

Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine–treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation.

Background: The last two decades have seen a great advance in the data that supports the two current hypotheses in Alzheimer's disease field, the amyloid beta hypothesis and the tau hypothesis. Not surprisingly, Aβ and tau proteins are currently the major therapeutic research targets for AD treatment. Unfortunately, nothing but moderate success has emerged from such therapeutic approaches. With this in mind, we will discuss deep brain stimulation as a promising therapeutic strategy that aims to restore brain activity. Lastly, in the scope of cognitive deficit restoration, we will discuss the relevance of the limbic formation as a promising neuroanatomical target for deep brain stimulation. Methods: Immunohistochemistry for modified tau (phosphorylated at Ser199–202–Thr205 labelled by the antibody AT8) was performed on paraffin-embedded human brain sections providing a detailed characterization of NFT pathology. Results: Abnormally phosphorylated tau protein is the key common marker in several brain diseases such as Alzheimer's disease, Parkinson's disease, Pick Disease, Down syndrome and frontotemporal dementia and is capable of affecting synaptic events that are critical for memory formation. With this in mind, therapeutic strategies aiming to restore synaptic events could offer better outcomes. Conclusion: The humble success of current therapeutic strategies along with the lack of basic knowledge of the brain disease mechanisms calls for alternatives that benefit patients in the present moment. One of particular interest is the neurostimulation strategy that is already a well-established treatment for several movement disorders and when compared to current Alzheimer's therapeutic strategies, deep brain stimulation does not directly interfere with the normal protein function, therefore increasing the probability of success.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, which are believed to lead to neural damage that translates into brain dysfunction and cognitive deficits. Brain dysfunction can be evaluated by measuring single-neuron activity (spikes), global neural activity (local field potentials, LFPs) and the interaction between them. Considering that the dynamic interactions between the hippocampal pyramidal cells and lateral septum are important for proper structure function, we used the complete septo-hippocampal preparation from 30-day-old controls and J20-AD transgenic mice to record changes in spiking activity from the lateral septum and its relationship with LFP activity from the CA1 area. The cross-correlation analysis revealed that young J20 transgenic mice exhibit a significant reduction in coupling between lateral septum single-cell activity and neural network activity from the hippocampal CA1. Consistently, phase-lock analysis between lateral septum single-cell activity and CA1 neural network activity showed lower values in J20 transgenic mice. Similarly, the LFP- LFP coherence between CA1 and septum in the theta range showed lower values in J20 animals. Importantly, alterations were found before any detectable signs of cognitive deficits. Our data indicate that the disruption in the communication between hippocampus and rostral lateral septum is an early event in AD pathology and may contribute to the deficits observed during AD.

International audience; Interneurons, key regulators of hippocampal neuronal network excitability and synchronization, are lost in advanced stages of Alzheimer's disease (AD). Given that network changes occur at early (presymptomatic) stages, we explored whether alterations of interneurons also occur before amyloid-beta (Aβ) accumulation. Numbers of neuropeptide Y (NPY) and parvalbumin (PV) immunoreactive (IR) cells were decreased in the hippocampus of 1 month-old TgCRND8 mouse AD model in a sub-regionally specific manner. The most prominent change observed was a decrease in the number of PV-IR cells that selectively affected CA1/2 and subiculum, with the pyramidal layer (PY) of CA1/2 accounting almost entirely for the reduction in number of hippocampal PV-IR cells. As PV neurons were decreased selectively in CA1/2 and subiculum, and given that they are critically involved in the control of hippocampal theta oscillations, we then assessed intrinsic theta oscillations in these regions after a 4-aminopyridine (4AP) challenge. This revealed increased theta power and population bursts in TgCRND8 mice compared to non-transgenic (nTg) controls, suggesting a hyperexcitability network state. Taken together, our results identify for the first time AD-related alterations in hippocampal interneuron function as early as at 1 month of age. These early functional alterations occurring before amyloid deposition may contribute to cognitive dysfunction in AD.

Aims Phosphorylation, conformational changes and cleavage of tau protein have been widely suggested to contribute to abnormal tau processing in the pathogenesis of Alzheimer's disease, as well as in other tauopathies. Consistently, many phosphorylated sites, such as Ser199–202–Thr205 and Ser396–404, have been associated with this pathological processing. The present study examined the chronological appearance of phosphorylation during the neurofibrillary tangle (NFT) evolution in Alzheimer disease (AD) and Down syndrome. Methods Immunohistochemistry for modified tau [phosphorylated at Ser199–202–Thr205 (AT8) and Ser396–404 (PHF-1) or truncated at D421 (TauC3) and E391 (MN423)] was performed on paraffin-embedded human brain sections. Double immunofluorescence for phosphorylated and truncated tau was used to detect intensity and distribution of tau immunoreactivity, and provided detailed characterization of NFT pathology. Results Phosphorylation at sites Ser396–404 was significantly increased when compared with phosphorylations at sites Ser199–202–Thr205. Around 50% of the total structures containing phosphorylation at sites Ser396–404 were found as early phospho-tau aggregates with a well-preserved neuronal soma. Phosphorylation of tau protein at sites Ser396 coexists with early and late truncation events. Tau abnormal processing in Down syndrome consistently showed similar alterations as observed in AD. Conclusion Phosphorylation of tau protein at the carboxyl terminus may be among the earliest tau events, and it occurs prior to the apparition of the classical fibrillar structure. Finally, these data validate PHF-1 as an efficient marker for AD cytopathology following the progression of tau aggregation into NFT.

Alzheimer’s disease (AD) is defined by the concurrence of abnormal aggregates composed of phosphorylated tau protein and of abnormal cellular changes including neurite degeneration, loss of neurons, and loss of cognitive functions. While a number of mechanisms have been implicated in this complex disease, oxidative stress remains one of the earliest and strongest events related to disease progression. However, the mechanism that links oxidative stress and cognitive decline remains elusive. Here, we propose that phosphorylated tau protein could be playing the role of potential connector and, therefore, that a combined therapy involving antioxidants and check points for synaptic plasticity during early stages of the disease could become a viable therapeutic option for AD treatment.

Amyloid plaques and neurofibrillary tangles are the hallmarks of Alzheimer’s disease and have been the focus of disease etiology and pathogenesis. However, in the larger picture of a complex disease, the precise etiology of the lesions per se, as well as the clinical disease, remain to be defined. In this regard, to date no single process has been identified as a useful target and treatment efforts have shown no meaningful progress. Therefore, alternative ideas that may lead to new and effective treatment options are much needed.

In the past, post-translational modifications of tau protein, such as phosphorylation, cleavage and conformational changes, have long been implicated in the pathogenesis of Alzheimer’s disease. Unfortunately, the accurate role and relationship between these pathological modifications during tau aggregation remains under extensive study. We had proposed a chronological model of tau pathological processing during Alzheimer´s disease, in which phosphorylation and cleavage could lead to conformational changes causing aggregation and therefore, cell toxicity. We discuss this issue and review in vitro and in situ evidence that supports the relevance of tau modifications that cause its pathological conformations and toxic aggregation. Thus, we offer a brief discussion regarding conformational change and cleavage as future clinical targets.

Abnormal posttranslational modifications of tau protein lead it to aggregate into paired helical filaments in Alzheimer's disease (AD). The mechanisms involved in the early pathological processing of tau and the induction of a polymeric state seem to progress through a sequential pattern of changes mainly involving abnormal phosphorylation, conformational changes and truncation. While proteolytic cleavage of tau protein during the progression of AD has not been comprehensively analyzed, tau is a substrate for several intracellular proteases. Furthermore, abnormal regulation of proteolytic events, including those associated with apoptosis, may generate truncated tau subproducts which in turn may be toxic to neurons per se and capable of polymerization at a faster rate. Accumulation of tau fibrils has long been controversial, with much debate concerning the true toxicity of polymerized tau. The development of different transgenic mice overexpressing tau protein, the generation of cell models expressing tau, and the in vitro polymerization paradigms have significantly enhanced our understanding of the biophysics and pathological properties of tau polymers in AD, as well as in other tau pathologies. This review will discuss the pathological role of truncated tau protein in the context of toxicity and neurofibrillary tangle formation and maturation and its significance in clinical dementia.

Amyloid-β and tau protein are the two most prominent factors in the pathology of Alzheimer disease. Recent studies indicate that phosphorylated tau might affect synaptic function. We now show that endogenous tau is found at postsynaptic sites where it interacts with the PSD95-NMDA receptor complex. NMDA receptor activation leads to a selective phosphorylation of specific sites in tau, regulating the interaction of tau with Fyn and the PSD95-NMDA receptor complex. Based on our results, we propose that the physiologically occurring phosphorylation of tau could serve as a regulatory mechanism to prevent NMDA receptor overexcitation.

Glycogen synthase kinase 3 (GSK3) has been implicated in neurological disorders; therefore, it is not surprising that there has been an increased focus towards developing therapies directed to this kinase. Unfortunately, these current therapies have not taken into consideration the physiological role of GSK3 in crucial events like synaptic plasticity. With this in mind we will discuss the relationship of synaptic plasticity with GSK3 and tau protein and their role as potential targets for the development of therapeutic strategies. Finally, we will provide perspectives in developing a cocktail therapy for Alzheimer's treatment.

Alzheimer’s disease (AD) is defined by the concurrence of accumulation of abnormal aggregates composed of two proteins: Amyloid beta (Aβ) and tau, and of cellular changes including neurite degeneration and loss of neurons and cognitive functions. Based on their strong association with disease, genetically and pathologically, it is not surprising that there has been a focus towards developing therapies against the aggregated structures. Unfortunately, current therapies have but mild benefit. With this in mind we will focus on the relationship of synaptic plasticity with Aβand tau protein and their role as potential targets for the development of therapeutic drugs. Finally, we will provide perspectives in developing a multifactorial strategy for AD treatment.

Abnormal aggregation of tau protein within the cytoplasm of susceptible neurons has been considered one of the major hallmarks that define the neuropathology of Alzheimer’s disease (AD) (Iqbal et al., 2010; Pritchard et al., 2011). At early stages of neuronal degeneration tau protein is accumulated in the form of early non-assembled aggregates that may alter the normal functioning of affected neurons (Hoozemans et al., 2009; Luna-Munoz et al., 2007). Nonfibrillar aggregation of tau protein as a pre-tangle state has been reported to occur early in the disease but also observed in nondemented very old individuals (Garcia-Sierra et al., 2000). Some studies have reported that oligomeric species of tau protein represent the toxic structures rather than fibrillary structures (Berger et al., 2007; Maeda et al., 2006), however few studies have analyzed and determined a positive correlation between the load of pre-tangle carrying neurons and the clinical symptoms of AD. Further alterations in neurons may occur when the soluble aggregates of tau become assembled into insoluble polymers referred to as paired helical filaments (PHFs) that may also obstruct the transit and distribution of intracellular components, modify the neuronal morphology and alter the cytoskeleton (Ballatore, Lee & Trojanowski, 2007; Kidd, 2006). These filaments progressively coalesce into neurofibrillary tangles (NFTs) which eventually lead to the neuronal death (Guo & Lee, 2011). It is generally accepted that in AD cases, the density of NFTs is the best correlate with the dementia score (Arriagada, Marzloff & Hyman, 1992; Gomez-Isla et al., 1997).

Oxidative stress is an early event in the development of Alzheimer disease (AD), preceding classic fibril formation which eventually deposits as amyloid-β senile plaques and neurofibrillary tangles composed of tau protein. Mitochondrial and metallic abnormalities are likely precursors of oxidative stress during the early stages of AD and, under degenerative conditions, the capacity of neurons to maintain redox balance decreases and results in mitochondrial dysfunction, a critical organelle involved in AD progression. Fibril formation, including amyloid-β production and tau phosphorylation, can be explained as a compensatory mechanism that may eventually enhance oxidative stress by increasing reactive oxygen species levels among many other free radicals. In this scenario, deposition of Aβ in the extracellular environment and tau protein in the intracellular environment can be explained as a redox imbalance with tragic consequences. If this hypothesis is correct, pharmacological treatments directed against amyloid-β or tau may not provide a benefit. In contrast, antioxidant strategies may be helpful in treating AD symptoms, although significant extended benefits have not been realized to date. In sum, the damage observed in the brain tissue of AD patients may be minimized with a healthy daily diet, exercise, and intellectual activities, factors that all reduce oxidative stress.

Phosphorylation, cleavage and conformational changes in tau protein all play pivotal roles during Alzheimer's disease (AD). In an effort to determine the chronological sequence of these changes, in this study, using confocal microscopy, we compared phosphorylation at several sites (Ser(199/202/396/404/422)-Thr(205) and the second repeat domain), cleavage of tau (D(421)) and the canonical conformational Alz-50 epitope. While all of these posttranslational modifications are found in neurofibrillary tangles (NFTs) at all stages of the disease, we found significantly higher numbers of phospho-tau positive NFTs when compared with cleaved tau (P = 0.006 in Braak III; P = 0.002 in Braak IV; P = 0.012 in Braak V) or compared with the Alz-50 epitope (P0.05). Consistent with these findings, in a double transgenic mice model (Tet/GSK-3beta/VLW) overexpressing the enzyme glycogen synthase kinase-3beta (GSK-3beta) and tau with a triple FTDP-17 mutation (VLW) with AD-like neurodegeneration, phosphorylation at sites Ser(199/202)-Thr(205) was greater than truncated tau. Taken together, these data strongly support the notion that the conformational changes and truncation of tau occur after the phosphorylation of tau. We propose two probable pathways for the pathological processing of tau protein during AD, either phosphorylation and cleavage of tau followed by the Alz-50 conformational change or phosphorylation followed by the conformational change and cleavage as the last step.

In Alzheimer’s disease, tau protein is abnormally processed to self-aggregate into pathologically paired helical filaments and neurofibrillary tangles. Accumulation of these structures in the somatodendritic compartment of neurons may result in pathological alterations of the cytoskeleton stability, abnormal sorting of molecules and obstruction of the intracellular transport of organelles. Initially, abnormal phosphorylation of tau was considered by many to be the major modification that alters its microtubule-binding capacity. In recent years, however, proteolytic cleavage of tau protein produced by caspases has been shown to promote the abnormal aggregation properties of tauin vitroand to produce toxic effects in cell and animal models of Alzheimer's disease. Although some of these results have been debated, truncation of tau associated with neurofibrillary tangle formation has been shown to correlate well with the clinical progression of Alzheimer’s disease. Although new alternative mechanisms of tau pathogenesis in a monomeric or oligomeric state have been proposed, the aggregated form of intact or truncated tau into insoluble polymers is still a major indicator of neuronal degeneration.

Background In Alzheimer disease (AD), hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities. Our prior ultra-morphometric studies documented a clear reduction in microtubules in pyramidal neurons in AD compared to controls, however, this reduction did not coincide with the presence of paired helical filaments. The latter suggests the presence of compensatory mechanism(s) that stabilize microtubule dynamics despite the loss of tau binding and stabilization. Microtubules are composed of tubulin dimers which are subject to posttranslational modifications that affect the stability and function of microtubules. Methods In this study, we performed a detailed analysis on changes in the posttranslational modifications in tubulin in postmortem human brain tissues from AD patients and age-matched controls by immunoblot and immunocytochemistry. Results Consistent with our previous study, we found decreased levels of α-tubulin in AD brain. Levels of tubulin with various posttranslational modifications such as polyglutamylation, tyrosination, and detyrosination were also proportionally reduced in AD brain, but, interestingly, there was an increase in the proportion of the acetylated α-tubulin in the remaining α-tubulin. Tubulin distribution was changed from predominantly in the processes to be more accumulated in the cell body. The number of processes containing polyglutamylated tubulin was well preserved in AD neurons. While there was a cell autonomous detrimental effect of NFTs on tubulin, this is likely a gradual and slow process, and there was no selective loss of acetylated or polyglutamylated tubulin in NFT-bearing neurons. Conclusions Overall, we suggest that the specific changes in tubulin modification in AD brain likely represent a compensatory response.