Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice.

Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with the P301L tau mutation (e.g., progressive supranuclear palsy and frontotemporal dementia). The P301L mutation makes tau prone to aggregation; therefore, JNPL3 mice present a more challenging target than mouse models of human tau without mutations. JNPL3 mice were treated from 3 to 7 months of age with Vehicle, 30 mg/kg compound dose, or 40 mg/kg compound dose. Biochemical methods were used to evaluate self-associated tau, insoluble tau aggregates, total tau, and phosphorylated tau in the hindbrain, cortex, and hippocampus. The Vehicle group had higher levels of insoluble tau in the hindbrain than the Baseline group; treatment with 40 mg/kg compound dose prevented this increase. In the cortex, the levels of insoluble tau were similar in the Baseline and Vehicle groups, indicating that the pathological phenotype of these mice was beginning to emerge at the study endpoint and that there was a delay in the development of the phenotype of the model as originally characterized. No drug-related adverse effects were observed during the 4-month treatment period.

Espresso Coffee Mitigates the Aggregation and Condensation of Alzheimer's Associated Tau Protein.

Espresso coffee is among the most consumed beverages in the world. Recent studies report a protective activity of the coffee beverage against neurodegenerative disorders such as Alzheimer's disease. Alzheimer's disease belongs to a group of disorders, called tauopathies, which are characterized by the intraneuronal accumulation of the microtubule-associated protein tau in fibrillar aggregates. In this work, we characterized by NMR the molecular composition of the espresso coffee extract and identified its main components. We then demonstrated with in vitro and in cell experiments that the whole coffee extract, caffeine, and genistein have biological properties in preventing aggregation, condensation, and seeding activity of the repeat region of tau. We also identified a set of coffee compounds capable of binding to preformed tau fibrils. These results add insights into the neuroprotective potential of espresso coffee and suggest candidate molecular scaffolds for designing therapies targeting monomeric or fibrillized forms of tau.

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

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

Immature Persimmon Suppresses Amyloid Beta (Aß) Mediated Cognitive Dysfunction via Tau Pathology in ICR Mice.

This study confirmed the ameliorating effect of immature persimmon (Diospyros kaki) ethanolic extract (IPEE) on neuronal cytotoxicity in amyloid beta (Aß)1-42-induced ICR mice. The administration of IPEE ameliorated the cognitive dysfunction in Aß1-42-induced mice by improving the spatial working memory, the short-term and long-term memory functions. IPEE protected the cerebral cholinergic system, such as the acetylcholine (ACh) level and acetylcholinesterase (AChE) activity, and antioxidant system, such as the superoxide dismutase (SOD), reduced glutathione (GSH) and malondialdehyde (MDA) contents. In addition, mitochondrial dysfunction against Aß1-42-induced toxicity was reduced by regulating the reactive oxygen species (ROS), mitochondrial membrane potential and ATP contents. In addition, IPEE regulated the expression levels of tau signaling, such as TNF-α, p-JNK, p-Akt, p-GSK3ß, p-tau, p-NF-κB, BAX and caspase 3. Finally, gallic acid, ellagic acid and quercetin 3-O-(6″-acetyl-glucoside) were identified as the physiological compounds of IPEE using ultra-performance liquid chromatography ion mobility separation quadrupole time-of-flight/tandem mass spectrometry (UPLC IMS Q-TOF/MS2).

Cognitive effects of the GSK-3 inhibitor "lithium" in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy.

Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto. METHODS: This study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-3ß (GSK-3ß) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition. RESULTS: LPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-3ß expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMS-induced depressive and cognitive deficits, reduced GSK-3ß over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival. CONCLUSION: This study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior low-dose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK-3ß inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.

Cognitive enhancement, TAU phosphorylation reduction, and neuronal protection by the treatment of an LRRK2 inhibitor in a tauopathy mouse model.

Leucine-rich repeat kinase 2 (LRRK2) is a protein kinase whose activity plays an important role in neurodegenerative diseases. Although mutations in LRRK2 gene are the most common cause of monogenic Parkinson's disease, it has been reported that LRRK2 may promote Tau phosphorylation, increasing its aggregation. Thus, the modulation of LRRK2 activity by small molecules able to inhibit this kinase activity could be an innovative therapeutic strategy for different tauopathies. We examined the therapeutic effects of a new benzothiazole-based LRRK2 inhibitor, known as JZ1.40, in a mouse model of tauopathy. Mice were injected in the right hippocampus with an adeno-associated vector expressing human-TAUP301L and treated daily with JZ1.40 (10 mg/kg, i.p) or vehicle for three weeks. JZ1.40 reaches the brain and modulates RAB10 and Tau phosphorylation at the epitopes modified by LRRK2. Moreover, JZ1.40 treatment ameliorates the cognitive impairment induced by TAUP301L overexpression, which correlates with prevention of granular cell layer degeneration by improving synaptic plasticity. These data show that JZ1.40 is neuroprotective in vivo, which is translated into cognition enhancement.

Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer's disease model.

In Alzheimer's disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aß) deposits. However, the effect of microtubule stabilizing agents on Aß pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aß accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aß levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aß pathology.

Neuronally expressed anti-tau scFv prevents tauopathy-induced phenotypes in Drosophila models.

We have derived single-chain variable fragments (scFv) from tau antibody hybridomas and previously shown their promise as imaging diagnostic agents. Here, we examined the therapeutic potential of anti-tau scFv in transgenic Drosophila models that express in neurons wild-type (WT) human tau (htau) or the human tauopathy mutation R406W. scFv expressing flies were crossed with the tauopathy flies and analyzed. Overall, the survival curves differed significantly (p < .0001). Control flies not expressing htau survived the longest, whereas R406W expressing flies had the shortest lifespan, which was greatly prolonged by co-expressing the anti-tau scFv (p < .0001). Likewise, htau WT expressing flies had a moderately short lifespan, which was prolonged by co-expressing the anti-tau scFv (p < .01). In addition, the htau expression impaired wing expansion after eclosion (p < .0001), and caused progressive abdomen expansion (p < .0001). These features were more severe in htau R406W flies than in htau WT flies. Importantly, both phenotypes were prevented by co-expression of the anti-tau scFv (p < .01-0.0001). Lastly, brain analyses revealed scFv-mediated tau clearance (p < .05-0.01), and its prevention of tau-mediated neurotoxicity (p < .05-0.001). In summary, these findings support the therapeutic potential of an anti-tau scFv, including as gene therapies, and the use of Drosophila models for such screening.

A Small Compound Targeting Prohibitin with Potential Interest for Cognitive Deficit Rescue in Aging mice and Tau Pathology Treatment.

Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1ß expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.

Inhibition of Calpain Protects Against Tauopathy in Transgenic P301S Tau Mice.

Alzheimer's disease (AD) and other tauopathies are characterized by intracellular accumulation of microtubule-associated tau protein leading to neurodegeneration. Calpastatin is the endogenous inhibitor of calpain, a calcium-dependent cysteine protease that has been increasingly implicated in tauopathies. In this study, we generated a neuron specific calpastatin overexpressing knock-in transgenic mouse model and crossed it with the PS19 tauopathy mouse model expressing human P301S mutant tau protein. The forced expression of calpastatin in neurons significantly alleviated tau hyperphosphorylation measured by immunocytochemistry and immunoblot. The genetic inhibition of calpain by calpastatin also greatly suppressed characteristic hippocampal neuron loss and widespread astrogliosis and microgliosis in PS19 mice. Consistently, PS19 mice with neuronal calpastatin overexpression exhibited remarkably alleviated cognitive deficits, muscle weakness, skeletal muscle atrophy, and neuromuscular denervation, together implying the neuroprotective effects of neuronal calpastatin in PS19 mice of tauopathy. In sum, this study provides additional evidence supporting the pathological role of calpain in neurodegenerative diseases associated with tau pathology, and suggests that targeting calpain is likely a promising therapeutic approach for these devastating diseases.

Topical ocular administration of the GLP-1 receptor agonist liraglutide arrests hyperphosphorylated tau-triggered diabetic retinal neurodegeneration via activation of GLP-1R/Akt/GSK3ß signaling.

Diabetic retinal neurodegeneration, in particular synaptic neurodegeneration of retinal ganglion cells (RGCs) occurring before RGCs apoptosis, may represent the earliest event in the pathogenesis of diabetic retinopathy (DR). Our previous study identified hyperphosphorylated-tau as a critical toxic mediator in diabetic RGCs synaptic neurodegeneration. Thus, therapeutic agents targeting to tau may appear as a promising strategy to arrest the progression of DR. The glucagon-like-peptide 1 receptor (GLP-1R) agonists, including liraglutide, can ameliorate neurodegenerative features in models of Alzheimer's disease and diabetes by decreasing tau hyperphosphorylation in the brain. Liraglutide has also been found to prevent retinal neural apoptosis/loss in diabetic mice. However, whether liraglutide can prevent diabetic synapse degeneration of RGCs, and its neuroprotective role, if any, is due to alleviating retinal tau hyperphosphorylation remain unknown. Here, using a well characterized high-fat diet (HFD)-induced diabetes mouse model, we showed that topical ocular administration of liraglutide reversed hyperphosphorylated tau-triggered RGCs synaptic degeneration in HFD-induced diabetes. The neuroprotective effect of liraglutide on diabetic retinae was abolished when GLP-1R or Akt was inhibited by topically co-administration with a GLP-1R antagonist, exendin-(9-39), or an Akt inhibitor MK2206, respectively. However, knock-down of GSK3ß by intravitreal injection of si-GSK3ß restored the neuroprotective effects of liraglutide abrogated by Akt inactivation. Thus, our present study demonstrated that liraglutide can arrest hyperphosphorylated tau-triggered retinal neurodegeneration via activation of GLP-1R/Akt/GSK3ß signaling. Our results also propose that topical ocular application of liraglutide can be envisaged as a potentially useful strategy for the treatment of retinal tauopathy at the early onset of DR.

The role of MAPK signaling pathway in selenium amelioration of high fat/high cholesterol diet-induced tauopathy in rats.

BACKGROUND: MAP kinases, CREB, and Tau are signaling molecules among downstream synaptic targets involved in synaptic function, memory formation and cognition. PURPOSE: Here we investigate the neuro-protective effect of selenium in HFHCD induced tauopathy and cognitive impairment in rats. The study was focused on the effects on synaptic plasticity related molecules in hippocampus, which in turn may be the mechanism responsible for underlying behavior alterations. METHOD: Rats were divided into 2 main groups: one fed with normal rat chow diet and the other with HFHCD for 6 weeks. Every group was subdivided into three subgroups, non-treated, low dose Se (200 µg/kg) and high dose Se (400 µg/kg). The cognitive behaviors of the rats were tested using the Morris Water Maze test, hole board and conditioned avoidance tests. RESULTS: Daily administration of Se decreased the observed memory impairment induced by HFHCD as measured by behavioral tests. It significantly alleviated oxidative stress and restored protein expression of cyclic AMP response element protein (CREB) and brain derived neurotrophic factor (BDNF) and reduced p-Tau in the hippocampus. CONCLUSION: Se reversed HFHCD-induced cognitive impairments via decrease expression of p38 MAPK that phosphorylate and aggregate Tau protein. Addition, It  restored neuronal plasticity through increasing the expression of BDNF, and CREB in the hippocampus; thus, it can be considered as a possible beneficial therapeutic approach for prevention and treatment of HFHCD induced tauopathy and cognitive impairment, further studies are warranted in this field.

Formulated Chinese Medicine Shaoyao Gancao Tang Reduces Tau Aggregation and Exerts Neuroprotection through Anti-Oxidation and Anti-Inflammation.

Misfolded tau proteins induce accumulation of free radicals and promote neuroinflammation by activating microglia-releasing proinflammatory cytokines, leading to neuronal cell death. Traditional Chinese herbal medicines (CHMs) have been widely used in clinical practice to treat neurodegenerative diseases associated with oxidative stress and neuroinflammation. This study examined the neuroprotection effects of formulated CHMs Bai-Shao (made of Paeonia lactiflora), Gan-Cao (made of Glycyrrhiza uralensis), and Shaoyao Gancao Tang (SG-Tang, made of P. lactiflora and G. uralensis at 1 : 1 ratio) in cell model of tauopathy. Our results showed that SG-Tang displayed a greater antioxidative and antiaggregation effect than Bai-Shao and Gan-Cao and a stronger anti-inflammatory activity than Bai-Shao but similar to Gan-Cao. In inducible 293/SH-SY5Y cells expressing proaggregant human tau repeat domain (ΔK280 tauRD), SG-Tang reduced tau misfolding and reactive oxygen species (ROS) level in ΔK280 tauRD 293 cells and promoted neurite outgrowth in ΔK280 tauRD SH-SY5Y cells. Furthermore, SG-Tang displayed anti-inflammatory effects by reducing nitric oxide (NO) production in mouse BV-2 microglia and increased cell viability of ΔK280 tauRD-expressing SH-SY5Y cells inflamed by BV-2 conditioned medium. To uncover the neuroprotective mechanisms of SG-Tang, apoptosis protein array analysis of inflamed tau expressing SH-SY5Y cells was conducted and the suppression of proapoptotic proteins was confirmed. In conclusion, SG-Tang displays neuroprotection by exerting antioxidative and anti-inflammatory activities to suppress neuronal apoptosis in human tau cell models. The study results lay the base for future applications of SG-Tang on tau animal models to validate its effect of reducing tau misfolding and potential disease modification.

Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo.

Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia.

Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.SIGNIFICANCE STATEMENT Accumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Aß accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the Δp35KI transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant Δp35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems.

Hsp90 activator Aha1 drives production of pathological tau aggregates.

The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer's disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood-brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau. Treatment with an Aha1 inhibitor, KU-177, dramatically reduced the accumulation of insoluble tau. Aha1 colocalized with tau pathology in human brain tissue, and this association positively correlated with AD progression. Aha1 overexpression in the rTg4510 tau transgenic mouse model promoted insoluble and oligomeric tau accumulation leading to a physiological deficit in cognitive function. Overall, these data demonstrate that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90. This suggests that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression.

Time course of Tau toxicity and pharmacologic prevention in a cell model of Tauopathy.

The aggregation of Tau protein is a hallmark of neurodegenerative diseases including Alzheimer's disease. Previously, we generated a cell model of tauopathy based on the 4-repeat domain with the FTDP-17 mutation ΔK280 (Tau4RDΔK) which is expressed in a regulatable fashion (tet-on). The deletion variant ΔK280 is highly amyloidogenic and forms fibrous aggregates in neuroblastoma N2a cells staining with the reporter dye Thioflavin S. The aggregation of Tau4RDΔK is toxic, contrary to wildtype or anti-aggregant variants of the protein. Using a novel approach for monitoring in situ Tau aggregation and toxicity by combination of microscopic analysis with FACS and biochemical analysis of cells enabled the dissection of the aggregating species which cause a time-dependent increase of toxicity. The dominant initiating step is the dimerization of Tau4RDΔK which leads to further aggregation and induces a strong increase in reactive oxygen species (ROS) and cytoplasmic Ca2+ which damage the membranes and cause cell death. Tau-based treatments using Tau aggregation inhibitors reduce both soluble oligomeric and fully aggregated Tau species and decrease their toxicity.

Prevention of Amyloid-ß and Tau Pathologies, Associated Neurodegeneration, and Cognitive Deficit by Early Treatment with a Neurotrophic Compound.

To date, neither any effective treatment nor prevention of Alzheimer's disease (AD), a major dementia causing disorder, are available. Herein, we investigated the secondary prevention of neurodegeneration, amyloid-ß (Aß) and tau pathologies with a neurotrophic compound P021 in 3xTg-AD mice. Previous work found that P021 can rescue at mild to moderate stages Aß and tau pathologies in 3xTg-AD mice. To determine its potential clinical application, we sought to test the preventive effect of P021 on Aß and tau pathologies by starting the treatment during the period of synaptic compensation several months before the appearance of any overt pathology in 3xTg-AD mice. We started a continuous treatment with P021 in 3-month-old female animals and followed its effect at 9-, 15- and 18-months post-treatment. Neurodegeneration at the above time points was studied using Fluorojade C staining, and tau and Aß pathologies both immunohistochemically and by Western blots. Cognitive performance was studied by assessing episodic memory with Novel Object Recognition task at 16-17-months post-treatment. We found that P021 treatment initiated during the synaptic compensation period can prevent neurodegeneration, Aß and tau pathologies, rescue episodic memory impairment, and markedly reduce mortality rate. These findings for the first time show effective prevention of AD changes with a neurotrophic compound that targets neurogenesis and synaptic plasticity, suggesting that improving the health of the neuronal network can prevent AD.

Vectored Intracerebral Immunization with the Anti-Tau Monoclonal Antibody PHF1 Markedly Reduces Tau Pathology in Mutant Tau Transgenic Mice.

Passive immunization with anti-tau monoclonal antibodies has been shown by several laboratories to reduce age-dependent tau pathology and neurodegeneration in mutant tau transgenic mice. These studies have used repeated high weekly doses of various tau antibodies administered systemically for several months and have reported reduced tau pathology of ∼40-50% in various brain regions. Here we show that direct intrahippocampal administration of the adeno-associated virus (AAV)-vectored anti-phospho-tau antibody PHF1 to P301S tau transgenic mice results in high and durable antibody expression, primarily in neurons. Hippocampal antibody levels achieved after AAV delivery were ∼50-fold more than those reported following repeated systemic administration. In contrast to systemic passive immunization, we observed markedly reduced (≥80-90%) hippocampal insoluble pathological tau species and neurofibrillary tangles following a single dose of AAV-vectored PHF1 compared with mice treated with an AAV-IgG control vector. Moreover, the hippocampal atrophy observed in untreated P301S mice was fully rescued by treatment with the AAV-vectored PHF1 antibody. Vectored passive immunotherapy with an anti-tau monoclonal antibody may represent a viable therapeutic strategy for treating or preventing such tauopathies as frontotemporal dementia, progressive supranuclear palsy, or Alzheimer's disease. SIGNIFICANCE STATEMENT: We have used an adeno-associated viral (AAV) vector to deliver the genes encoding an anti-phospho-tau monoclonal antibody, PHF1, directly to the brain of mice that develop neurodegeneration due to a tau mutation that causes frontotemporal dementia (FTD). When administered systemically, PHF1 has been shown to modestly reduce tau pathology and neurodegeneration. Since such antibodies do not readily cross the blood-brain barrier, we used an AAV vector to deliver antibody directly to the hippocampus and observed much higher antibody levels and a much greater reduction in tau pathology. Using AAV vectors to deliver antibodies like PHF1 directly to brain may constitute a novel approach to treating various neurodegenerative disorders, such as FTD and Alzheimer's disease.