Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer’s disease

Since abnormal post-translational modifications or gene mutations of tau have been detected in over twenty neurodegenerative disorders, tau has attracted widespread interest as a target protein. Among its various post-translational modifications, phosphorylation is the most extensively studied. It is recognized that tau hyperphosphorylation is the root cause of neurodegeneration in Alzheimer’s disease (AD); however, it is not clear how it causes neurodegeneration. Based on the findings that tau hyperphosphorylation leads to the escape of neurons from acute apoptosis and simultaneously impairs the function of neurons, we have proposed that the nature of AD neurodegeneration is the consequence of aborted apoptosis induced by tau phosphorylation. Therefore, proper manipulation of tau hyperphosphorylation could be promising for arresting AD neurodegeneration. In this review, the neuroprotective and neurodegenerative effects of tau hyperphosphorylation and our thoughts regarding their relationship are presented.     

Tau phosphorylation in Alzheimer’s disease

The two predominant pathological concomitants of Alzheimer’s disease (AD) are senile plaques and neurofibrillary tangles. Although many biochemical studies have addressed the composition and formation of these AD hallmarks, very little is known about the interrelationship between the two. Here we present evidence that the tau phosphorylation characteristic of neurofibrillary tangles may be mediated by a physical association of MKK6 (mitogen-associated protein kinase kinase 6) with tau and subsequent phosphorylation of tau by the MKK6 substrate, p38 MAPK; and that APP (β-amyloid precursor protein) may be co-immunoprecipitated both with MKK6 and its upstream MAPKKK, ASK1. Taken together with recent data demonstrating APP dimerization by β-amyloid peptide (Aβ) (Lu et al., 2003), and the possible activation of ASK1 via APP dimerization (Hashimoto et al., 2003), these results suggest a model of AD in which Aβ peptide dimerizes APP directly, leading to the activation of ASK1, MKK6, and p38, with subsequent phosphorylation of tau at sites characteristic of AD.     

Sodium selenate specifically activates PP2A phosphatase,dephosphorylates tau and reverses memory deficits in an Alzheimer’s disease model

Neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein are a hallmark of Alzheimer’s disease (AD) and related tauopathies. Tau hyperphosphorylation is thought to promote aggregation with subsequent tangle formation. Reducing tau phosphorylation by boosting the activity of the key phosphatase/s that mediate dephosphorylation of tau could be a viable clinical strategy in AD. One of the key phosphatases implicated in regulating tau protein phosphorylation is the serine–threonine phosphatase PP2A. We have determined that sodium selenate can act as a specific agonist for PP2A, significantly boosting phosphatase activity. Acute treatment of either neuroblastoma cells or normal aged mice with sodium selenate rapidly reduced tau protein phosphorylation. Sodium selenate-treated transgenic TAU441 mice had significantly lower levels of phospho- and total tau levels in the hippocampus and amygdala compared with controls and exhibited significantly improved spatial learning and memory on the Morris Water Maze task. Sodium selenate is a specific activator of PP2A with excellent oral bioavailability, and favourable central nervous system penetrating properties. Clinical studies in patients with AD are envisaged in the near future.     

Phosphorylation of soluble tau differs in Pick’s disease and Alzheimer’s disease brains

Frontotemporal lobar degeneration (FTLD) is a common cause of presenile dementia characterised by behavioural and language disturbances. Pick’s disease (PiD) is a subtype of FTLD, which presents with intraneuronal inclusions consisting of hyperphosphorylated tau protein aggregates. Although Alzheimer’s disease (AD) is also characterised by tau lesions, these are both histologically and biochemically distinct from the tau aggregates found in PiD. What determines the distinct characteristics of these tau lesions is unknown. As phosphorylated, soluble tau has been suggested to be the precursor of tau aggregates, we compared both the level and phosphorylation profile of tau in tissue extracts of AD and PiD brains to determine whether the differences in the tau lesions are reflected by differences in soluble tau. Levels of soluble tau were decreased in AD but not PiD. In addition, soluble tau was phosphorylated to a greater extent in AD than in PiD and displayed a different phosphorylation profile in the two disorders. Consistently, tau kinases were activated to different degrees in AD compared with PiD. Such differences in solubility and phosphorylation may contribute, at least in part, to the formation of distinct tau deposits, but may also have implications for the clinical differences between AD and PiD.     

Pharmacological approaches of neurofibrillary degeneration

Alzheimer disease (AD) and related tauopathies are all characterized histopathologically by neurofibrillary degeneration. The neurofibrillary changes, whether of paired helical filaments (PHF), twisted ribbons or straight filaments (SF) are made up of abnormally hyperphosphorylated tau. Unlike normal tau which promotes assembly and maintains structure of microtubules, the abnormal tau not only lacks these functions but also sequesters normal tau, MAP1 and MAP2, and causes disassembly of microtubules. This toxic behavior of the abnormal tau is solely due to its hyperphosphorylation because dephosphorylation restores it into a normal-like protein. The abnormal hyperphosphorylation also promotes the self-assembly of tau into PHF/SF. The state of phosphorylation of a phosphoprotein is the function of the activities of protein kinases and as well as of protein phosphatases that regulate the level of phosphorylation. A cause of the abnormal hyperphosphorylation in AD brain is a decrease in the activity of protein phosphatase (PP)-2A, a major regulator of the phosphorylation of tau. A decrease in PP-2A activity results in the abnormal hyperphosphorylation of tau not only by decreased dephosphorylation of tau but also by stimulating the activities of tau kinases like CaMKII, PKA and MAP kinases which are regulated by PP-2A. Thus, the abnormal hyperphosphorylation can be inhibited both by inhibition of the activity/s of a tau protein kinase and as well as by restoration of the activity/s of a tau protein phosphatase. The development of drugs that inhibit neurofibrillary degeneration is a very promising and feasible therapeutic approach to inhibit the progression of AD and related tauopathies.     

p44mpk MAP kinase induces aizheimer type alterations in tau function and in primary hippocampal neurons

Abnormally phosphorylated tau protein is a major component of the cytoskeletal pathology of Alzheimer's disease (AD) found in the neurofibrillary tangle (NFT) and neuritic plaque (NP). Identification of the kinase responsible for this phosphorylation has been difficult. In the test tube, several proline-directed kinases, particularly mitogen-activated protein (MAP) and cdc2 kinase, phosphorylate tau on sites that appear to mimic the abnormally phosphcrylated sites in AD. Important unanswered issues include: (1) whether this phosphorylation event occurs in the tightly regulated environment of a living cell; (2) whether this phosphorylation of tau affects its functional properties; and (3) what is the subcellular relationship of proline-directed kinases and tau. We show here that tau can be phosphorylated in cultured hippocampal neurons by the MAP kinase p^44mpk and phosphorylation of tau compromises its functional ability to assemble microtubules. We show further that MAP kinase copurifies with microtubule fractions where it is tyrosine phosphorylated and presumably active. These studies address and raise several important issues regarding the regulation of tau phosphorylation in normal and AD brain. © 1993 Wiley-Liss, Inc.     

Abnormal tau phosphorylation in the thorny excrescences of CA3 hippocampal neurons in patients with Alzheimer's disease

A key symptom in the early stages of Alzheimer's disease (AD) is the loss of declarative memory. The anatomical substrate that supports this kind of memory involves the neural circuits of the medial temporal lobe, and in particular, of the hippocampal formation and adjacent cortex. A main feature of AD is the abnormal phosphorylation of the tau protein and the presence of tangles. The sequence of cellular changes related to tau phosphorylation and tangle formation has been studied with an antibody that binds to diffuse phosphotau (AT8). Moreover, another tau antibody (PHF-1) has been used to follow the pathway of neurofibrillary (tau aggregation) degeneration in AD. We have used a variety of quantitative immunocytochemical techniques and confocal microscopy to visualize and characterize neurons labeled with AT8 and PHF-1 antibodies. We present here the rather unexpected discovery that in AD, there is conspicuous abnormal phosphorylation of the tau protein in a selective subset of dendritic spines. We identified these spines as the typical thorny excrescences of hippocampal CA3 neurons in a pre-tangle state. Since thorny excrescences represent a major synaptic target of granule cell axons (mossy fibers), such aberrant phosphorylation may play an essential role in the memory impairment typical of AD patients.     

Caspase-12 activation is involved in amyloid-β protein-induced synaptic toxicity

Aggregation of tau proteins followed by formation of paired helical filaments and neurofibrillary tangles is considered as a hallmark of certain neurodegenerative disorders such as different tauopathies and Alzheimer's disease (AD). Tau aggregation is dependent on the presence of polyanions, cellular redox state, limited proteolysis, and different posttranslational modifications among which tau phosphorylation plays a particularly important role. Although it is still debatable whether tau aggregation is harmful or protective for the cell, detailed analysis of molecular mechanisms underlying this process seems to be of great importance for understanding AD pathogenesis. This review is focused on universal adapter proteins 14-3-3 that seem to be significant partners to tau protein in neurons. 14-3-3 interacts with nonphosphorylated tau and promotes its interaction with and phosphorylation by a number of protein kinases. 14-3-3 induces aggregation of nonphosphorylated tau and does not affect aggregation of tau phosphorylated at specific sites. Due to its high concentration in neurons, 14-3-3 can compete with tubulin for interaction with tau. Binding to phosphorylated tau, 14-3-3 might inhibit its dephosphorylation by protein phosphatases and by this means indirectly affect interaction of tau with microtubules and tau aggregation. Finally, 14-3-3 might promote sequestration of dangerous small tau oligomers and stabilize tau aggregates. We propose that 14-3-3 should be considered an important participant of the complex process of tau aggregation and as a potential therapeutic target in treating AD.     

Pharmacological targets to inhibit Alzheimer neurofibrillary degeneration

Neurofibrillary degeneration appears to be required for the clinical expression of Alzheimer disease (AD) and related tauopathies. Given the polyetiology of these diseases and the pivotal involvement of neurofibrillary degeneration in their pathogenesis, inhibition of this lesion offers a promising therapeutic target. Studies from our laboratories have shown that there is a protein phosphorylation/dephosphorylation imbalance and that the microtubule associated protein tau is abnormally hyperphosphorylated in the brain of patients with AD and in this form it is the major protein subunit of paired helical filaments/neurofibrillary tangles (PHF/NFT). The abnormal tau which is polymerized into PHF/NFT neither promotes or inhibits in vitro microtubule assembly. In contrast the cytosolic abnormally hyperphosphorylated tau from AD brain, the AD P-tau neither associates with tubulin nor promotes in vitro microtubule assembly but instead it sequesters normal tau, MAP1 and MAP2 and inhibits microtubule assembly. The AD P-tau readily self-assembles in vitro into tangles of PHF/straight filaments under physiological conditions of protein concentration, pH, ionic strength and reducing conditions and this self assembly requires the abnormal hyperphosphorylation of this protein. The activity of phosphoseryl/phosphothreonyl protein phosphatase (PP)-2A which regulates the phosphorylation of tau, is compromised in AD brain. Thus, modulation of the activities of protein phosphatase-2A and tau kinases and inhibition of the sequestration of normal MAPs by AD P-tau offer promising therapeutic opportunities to inhibit neurofibrillary degeneration and the diseases characterized by this lesion.     

Amyloid-β protein precursor regulates phosphorylation and cellular compartmentalization of microtubule associated protein tau

Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When hyperphosphorylated and aggregated in atrophic neurons, tau is considered the culprit for neuronal death in familial and sporadic tauopathies. With regards to Alzheimer's disease (AD) pathogenesis, it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration. In fact, it is unquestionably accepted that amyloid-β protein precursor (AβPP) plays a pivotal role in the genesis of the disease, and it is postulated that the formation of toxic amyloid-β peptides from AβPP is the primary event that subsequently induces abnormal tau phosphorylation. In this work, we show that in the brain of AD patients there is an imbalance between the nuclear and the cytoskeletal pools of phospho-tau. We observed that in non-AD subjects, there is a stable pool of phospho-tau which remains strictly confined to neuronal nuclei, while nuclear localization of phospho-tau is significantly underrepresented in neurons of AD patients bearing neurofibrillary tangles. A specific phosphorylation of tau is required during mitosis in vitro and in vivo, likely via a Grb2-ERK1/2 signaling cascade. In differentiated neuronal A1 cells, the overexpression of AβPP modulates tau phosphorylation, altering the ratio between cytoskeletal and nuclear pools, and correlates with cell death. Altogether our data provide evidence that AβPP, in addition to amyloid formation, modulates the phosphorylation of tau and its subcellular compartmentalization, an event that may lead to the formation of neurofibrillary tangles and to neurodegeneration when occurring in postmitotic neurons.     

Reversible in vivo phosphorylation of tau induced by okadaic acid and by unspecific brain lesion in rat

Alzheimer's disease (AD) is histopathologically characterised by the formation of neurofibrillary tangles (NFTs) that are largely composed of hyperphosphorylated tau protein (PHF-tau), and senile plaques which contain aggregates of the Abeta peptide. Formation of PHF-tau and amyloidogenic processing of the amyloid precursor protein (APP) might be related to a disturbance in the balance between protein phosphorylation and dephosphorylation. In the present study, the effects of injections into the cerebral cortex of either okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A, or saline were investigated. Both kinds of injections induced a reversible phosphorylation of tau, albeit to a different extent. The secretion of soluble APP was reduced after OA but not affected after injection of saline. It is concluded that phosphorylation of tau, similar though not identical to those seen in AD can be induced in vivo by inhibition of protein dephosphorylation as well as by unspecific lesion of cortical neurones. It might, therefore, be suggested that phosphorylation processes involved in PHF-formation in AD similarly reflect a neuronal response to injury.     

Tau as a therapeutic target for Alzheimer's disease

Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of Alzheimer's disease (AD) and are primarily composed of aggregates of hyperphosphorylated forms of the microtubule associated protein tau. It is likely that an imbalance of kinase and phosphatase activities leads to the abnormal phosphorylation of tau and subsequent aggregation. The wide ranging therapeutic approaches that are being developed include to inhibit tau kinases, to enhance phosphatase activity, to promote microtubule stability, and to reduce tau aggregate formation and/or enhance their clearance with small molecule drugs or by immunotherapeutic means. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase II clinical trials. By pursuing these lines of study, a viable therapy for AD and related tauopathies may be obtained.     

Hippocampal neurons predisposed to neurofibrillary tangle formation are enriched in type II calcium/calmodulin-dependent protein kinase

The microtubule-associated phosphoprotein, tau, is an integral component of paired helical filaments in Alzheimer neurofibrillary tangles (NFT). The mechanism of NFT formation is unknown but aberrant phosphorylation of tau may be contributory. Calcium/calmodulin-dependent protein kinase type II (CaM kinase II), the most abundant kinase in the brain, phosphorylates tau in vitro. We found CaM kinase II immunoreactivity concentrated in human hippocampal pyramidal neurons of CA1 and the subiculum. In Alzheimer's disease (AD) staining intensity of CA1 and subicular neurons is strikingly increased despite NFT formation and neuronal depletion. Enhanced CaM kinase II activity, possibly a result of deafferentation, may contribute to phosphorylation of tau protein leading to NFT deposition and neuronal death in AD.     

Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration

Microtubule associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and related tauopathies; in this form it is the major protein subunit of paired helical filaments (PHF)/neurofibrillary tangles. However, the nature of protein kinases and phosphatases and tau sites involved in this lesion has been elusive. We investigated self-assembly and microtubule assembly promoting activities of hyperphosphorylated tau isolated from Alzheimer disease brain cytosol, the AD abnormally hyperphosphorylated tau (AD P-tau) before and after dephosphorylation by phosphoseryl/phosphothreonyl protein phosphatase-2A (PP-2A), and then rephosphorylation by cyclic AMP-dependent protein kinase (PKA), calcium, calmodulin-dependent protein kinase II (CaMKII), glycogen synthase kinase-3beta (GSK-3beta) and cyclin-dependent protein kinase 5 (cdk5) in different kinase combinations. We found that (i) dephosphorylation of AD P-tau by PP-2A inhibits its polymerization into PHF/straight filaments (SF) and restores its binding and ability to promote assembly of tubulin into microtubules; (ii) rephosphorylation of PP-2A-dephosphorylated AD P-tau by sequential phosphorylation by PKA, CaMKII and GSK-3beta or cdk5, and as well as by cdk5 and GSK-3beta, promotes its self-assembly into tangles of PHF similar to those seen in Alzheimer brain, and (iii) phosphorylation of tau sites required for this pathology are Thr231 and Ser262, along with several sites flanking the microtubule binding repeat region. Phosphorylation of recombinant human brain tau(441) yielded similar results as the PP-2A dephosphorylated AD P-tau, except that mostly SF were formed. The conditions for the abnormal hyperphosphorylation of tau that promoted its self-assembly also induced the microtubule assembly inhibitory activity. These findings suggest that activation of PP-2A or inhibition of either both GSK-3beta and cdk5 or one of these two kinases plus PKA or CaMKII might be required to inhibit Alzheimer neurofibrillary degeneration.     

Truncation of tau protein and its pathological significance in Alzheimer's disease

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.     

Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting

Impaired brain glucose uptake/metabolism precedes the symptoms of Alzheimer disease (AD) and is likely to play a role in the development of the disease, but the mechanism by which it contributes to AD is not understood. Because glucose uptake/metabolism regulates protein O-GlcNAcylation, and the latter modulates phosphorylation of tau inversely, we investigated, in fasting Kunming mice, whether impaired brain glucose uptake/metabolism causes abnormal hyperphosphorylation of tau and, consequently, facilitates the neurofibrillary degeneration of AD via down-regulation of tau O-GlcNAcylation. We found that fasting caused decreased tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied. The hippocampus was found more vulnerable to the tau alterations than the cerebral cortex, which is consistent with the fact that it is the hippocampus that is first affected in AD. Furthermore, hyperphosphorylation of tau induced by fasting was reversible in the brain after re-feeding. These findings provide a novel mechanism explaining how impaired brain glucose uptake/metabolism contributes to AD and suggest that it may be feasible to treat AD by reversing the abnormal hyperphosphorylation of tau at early stages of the disease.     

Attenuation of β‐amyloid‐induced tauopathy via activation of CK2α/SIRT1: Targeting for cilostazol

β‐Amyloid (Aβ) deposits and hyperphosphorylated tau aggregates are the chief hallmarks in the Alzheimer's disease (AD) brains, but the strategies for controlling these pathological events remain elusive. We hypothesized that CK2‐coupled SIRT1 activation stimulated by cilostazol suppresses tau acetylation (Ac‐tau) and tau phosphorylation (P‐tau) by inhibiting activation of P300 and GSK3β. Aβ was endogenously overproduced in N2a cells expressing human APP Swedish mutation (N2aSwe) by exposure to medium containing 1% fetal bovine serum for 24 hr. Increased Aβ accumulation was accompanied by increased Ac‐tau and P‐tau levels. Concomitantly, these cells showed increased P300 and GSK3β P‐Tyr216 expression; their expressions were significantly reduced by treatment with cilostazol (3–30 μM) and resveratrol (20 μM). Moreover, decreased expression of SIRT1 and its activity by Aβ were significantly reversed by cilostazol as by resveratrol. In addition, cilostazol strongly stimulated CK2α phosphorylation and its activity, and then stimulated SIRT1 phosphorylation. These effects were confirmed by using the pharmacological inhibitors KT5720 (1 μM, PKA inhibitor), TBCA (20 μM, inhibitor of CK2), and sirtinol (20 μM, SIRT1 inhibitor) as well as by SIRT1 gene silencing and overexpression techniques. In conclusion, increased cAMP‐dependent protein kinase‐linked CK2/SIRT1 expression by cilostazol can be a therapeutic strategy to suppress the tau‐related neurodegeneration in the AD brain. © 2013 Wiley Periodicals, Inc.     

Brain-derived neurotrophic factor induces a rapid dephosphorylation of tau protein through a PI-3 Kinase signalling mechanism

The microtubule-associated protein tau is essential for microtubule stabilization in neuronal axons. Hyperphosphorylation and intracellular fibrillar formation of tau protein is a pathology found in Alzheimer's disease (AD) brains, and in a variety of neurodegenerative disorders referred to as 'taupathies'. In the present study, we investigated how brain-derived neurotrophic factor (BDNF), an extracellular factor that is down-regulated in AD brains, affects tau phosphorylation. BDNF stimulation of neuronally differentiated P19 mouse embryonic carcinoma cells resulted in a rapid decrease in tau phosphorylation, at phosphorylation sites recognized by Tau 1, AT 8, AT 180 and p 262-Tau antibodies. K 252 a, a tyrosine receptor kinase (Trk) inhibitor, attenuated this dephosphorylation event, suggesting that BNDF activation of TrkB is responsible for the tau dephosphorylation. In addition, BDNF had no affect on tau phosphorylation in the presence of wortmannin, a PI-3 Kinase inhibitor, or lithium, a GSK 3 beta inhibitor, suggesting that these two kinases are part of the signaling transduction cascade leading from TrkB receptor activation to tau dephosphorylation. These results suggest a link between a correlate of AD, decrease in BDNF levels and an AD pathology, tau hyperphosphorylation.     

Fast axonal transport misregulation and Alzheimer's disease

Pathological alterations in the microtubule-associated protein (MAP) tau are well-established in a number of neurodegenerative disorders, including Alzheimer’s Disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and others. Tau protein and in some cases, neurofilament subunits exhibit abnormal phosphorylation on specific serine and threonine residues in these diseases. A large body of biochemical, genetic, and cell biological evidence implicate two major serine-threonine protein kinases, glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase 5 (CDK5) as major kinases responsible for both normal and pathological phosphorylation of tau protein in vivo. What remains unclear is whether tau phosphorylation and/or neurofibrillary tangle (NFT) formation are causal or secondary to initiation of neuronal pathology. In fact, many studies have indicated that tau misphosphorylation is not the causal event. Interestingly, some of these kinase and phosphatase activities have recently merged as key regulators of fast axonal transport (FAT). Specifically, CDK5 and GSK-3 have been recently shown to regulate kinesin-driven motility. Given the essential role of FAT in neuronal function, an alternate model for pathogenesis can be proposed. In this model, misregulation of FAT induced by an imbalance in specific kinase-phosphatase activities within neurons represents an early and critical step for the initiation of neuronal pathology. Such a model may explain many of the unique characteristics of late onset of neurological diseases such as AD.     

Neuronal Life Span Versus Health Span: Principles of Natural Selection at Work in the Degenerating Brain

Impaired nutrient delivery to the brain due to decreased blood flow contributes to cognitive decline and dementia in Alzheimer’s disease (AD). Considering this, many studies have suggested that neuroprotective agents like those used in stroke could prevent AD onset or progression by promoting cell survival. However, research in the past decade suggests that the culprit behind the cognitive loss in AD models is actually the soluble tau accumulating inside of surviving neurons. In fact, tau reductions improve cognition in mouse models of AD, even those that only deposit amyloid plaques. There is emerging evidence that neuroprotection alone in these AD models may be insufficient to restore neuron function and cognition. Only when soluble tau is reduced on a neuroprotective background could memory be rescued. Thus, once a neuron begins to accumulate tau, it may survive in a malfunctioning capacity, leading to impaired electrical signaling and memory formation in the brain. These data imply that multiple drugs may be necessary to ameliorate the different disease components. In fact, strategies to preserve neurons without affecting the soluble protein burden within neurons may accelerate the disease course.