Neurodegenerative tauopathies, such as Alzheimer’s disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a Tg model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.
Tau, a protein that is enriched in neurons of the central nervous system (CNS)1, is thought to play a critical role in the stabilization of microtubules (MTs). Several neurodegenerative disorders referred to as tauopathies, including Alzheimer’s disease and certain types of frontotemporal lobar degeneration, are characterized by the intracellular accumulation of hyperphosphorylated tau fibrils. Tau deposition into insoluble aggregates is believed to result in a loss of tau function that leads to MT destabilization, and this could cause neurodegeneration as intact MTs are required for axonal transport and normal neuron function. This tau loss-of-function hypothesis has been validated in a tau transgenic mouse model with spinal cord tau inclusions, where the MT-stabilizing agent, paclitaxel, increased spinal nerve MT density and improved motor function after drug absorption at neuromuscular junctions. Unfortunately, paclitaxel is a P-glycoprotein substrate and has poor blood-brain barrier permeability, making it unsuitable for the treatment of human tauopathies. We therefore examined several MT-stabilizing compounds from the taxane and epothilone natural product families to assess their membrane permeability and to determine whether they act as substrates or inhibitors of P-glycoprotein. Moreover, we compared brain and plasma levels of the compounds after administration to mice. Finally, we assessed whether brain-penetrant compounds could stabilize mouse CNS MTs. We found that several epothilones have significantly greater brain penetration than the taxanes. Furthermore, certain epothilones cause an increase in CNS MT stabilization, with epothilone D demonstrating a favorable pharmacokinetic and pharmacodynamic profile which suggests this agent merits further study as a potential tauopathy drug candidate.
Alzheimer’s disease; microtubules; tauopathies; therapeutic
Neurons in the brains of those with Alzheimer's disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related “tauopathies” is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood-brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (epoD), is brain-penetrant and we subsequently evaluated whether epoD can compensate for tau loss-of-function in PS19 tau Tg mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month old male PS19 mice with low doses of epoD once-weekly for a 3-month period significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, epoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.
Tau; Microtubule; Blood-brain barrier; Alzheimer's disease; Learning and Memory; Transgenic
Inclusions comprised of fibrils of the microtubule (MT)-associated protein tau are found in the brains of those with Alzheimer’s disease (AD) and other neurodegenerative tauopathies. The pathology that is observed in these diseases is believed to result from the formation of toxic tau oligomers or fibrils, and/or from the loss of normal tau function due to its sequestration into insoluble deposits. Hence, small molecules that prevent tau oligomerization and/or fibrillization might have therapeutic value. Indeed, examples of such compounds have been published but nearly all have properties that render them unsuitable as drug candidates. For these reasons, we conducted quantitative high-throughput screening (qHTS) of ~292,000 compounds to identify drug-like inhibitors of tau assembly. The fibrillization of a truncated tau fragment that contains four MT-binding domains was monitored in an assay that employed complementary thioflavine T fluorescence and fluorescence polarization methods. Previously described classes of inhibitors as well as new scaffolds were identified, including novel aminothienopyridazines (ATPZ’s). A number of ATPZ analogs were synthesized and structure-activity relationships were defined. Further characterization of representative ATPZ compounds showed they do not interfere with tau-mediated MT assembly, and they are significantly more effective at preventing the fibrillization of tau than the Aβ(1–42) peptide which forms AD senile plaques. Thus, the ATPZ molecules described here represent a novel class of tau assembly inhibitors that merit further development for testing in animal models of AD-like tau pathology.
(MT) stabilizing drugs hold promise as potential treatments
for Alzheimer’s disease (AD) and related tauopathies. However,
thus far epothilone D has been the only brain-penetrant MT-stabilizer
to be evaluated in tau transgenic mice and in AD patients. Furthermore,
this natural product exhibits potential deficiencies as a drug candidate,
including an intravenous route of administration and the inhibition
of the P-glycoprotein (Pgp) transporter. Thus, the identification
of alternative CNS-active MT-stabilizing agents that lack these potential
limitations is of interest. Toward this objective, we have evaluated
representative compounds from known classes of non-naturally occurring
MT-stabilizing small molecules. This led to the identification of
selected triazolopyrimidines and phenylpyrimidines that are orally
bioavailable and brain-penetrant without disruption of Pgp function.
Pharmacodynamic studies confirmed that representative compounds from
these series enhance MT-stabilization in the brains of wild-type mice.
Thus, these classes of MT-stabilizers hold promise for the development
of orally active, CNS-directed MT-stabilizing therapies.
In Alzheimer’s disease (AD), an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau) antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs) comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19) led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies.
Small-molecule ligands, amenable to positron emission tomography (PET) imaging of different types of neurodegenerative disease-associated amyloid deposits in the CNS of living patients, hold considerable promise for diagnostic purposes, as well as for monitoring disease progression and the effectiveness of treatments. The patent entitled ‘Heterocyclic Compounds as Imaging Probes of Tau Pathology’ (WO2013090497) discloses the identification of a novel class of tau imaging agents, the aminothienopyridazines. Selected compounds from this class are described that can stain selectively tau pathology in brain tissue sections. Moreover, examples of this class of compounds exhibit absorption, distribution, metabolism, excretion and pharmacokinetics (ADME-PK) properties that are appropriate for CNS PET ligands.
Alzheimer’s disease; aminothienopyridazine; positron emission tomography; tau
Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day.
Alzheimer’s disease; Tauopathy; Aminothienopyridazine; Tau aggregation inhibitor; K18PL
Neurofibrillary tangles composed of hyperphosphorylated fibrillized tau are found in numerous tauopathies including Alzheimer's disease. Increasing evidence suggests that tau pathology can be transmitted from cell-to-cell; however the mechanisms involved in the initiation of tau fibrillization and spreading of disease linked to progression of tau pathology are poorly understood. We show here that intracerebral injections of preformed synthetic tau fibrils into the hippocampus or frontal cortex of young tau transgenic mice expressing mutant human P301L tau induces tau hyperphosphorylation and aggregation around the site of injection, as well as a time-dependent propagation of tau pathology to interconnected brain areas distant from the injection site. Furthermore, we show that the tau pathology as a consequence of injection of tau preformed fibrils into the hippocampus induces selective loss of CA1 neurons. Together, our data confirm previous studies on the seeded induction and the spreading of tau pathology in a different tau transgenic mouse model and reveals neuronal loss associated with seeded tau pathology in tau transgenic mouse brain. These results further validate the utility of the tau seeding model in studying disease transmission, and provide a more complete in vivo tauopathy model with associated neurodegeneration which can be used to investigate the mechanisms involved in tau aggregation and spreading, as well as aid in the search for disease modifying treatments for Alzheimer's disease and related tauopathies.
Seeding; Spreading; Tau pathology; Cell death
Inclusions comprising the microtubule
tau, are found within neurons in the brains of patients with Alzheimer’s
disease and related neurodegenerative disorders that are broadly referred
to as tauopathies. The sequestration of tau into inclusions is believed
to cause a loss of tau function, such that MT structure and function
are compromised, leading to neuronal damage. Recent data reveal that
the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), improves
cognitive function and decreases both neuron loss and tau pathology
in transgenic mouse models of tauopathy. There is thus a need to identify
additional MT-stabilizing compounds with blood–brain barrier
(BBB) permeability and slow brain clearance, as observed with EpoD.
We report here that the MT-stabilizing natural product, dictyostatin,
crosses the BBB in mice and has extended brain retention. Moreover,
a single administration of dictyostatin to mice causes prolonged stabilization
of MTs in the brain. In contrast, the structurally related MT-stabilizer,
discodermolide, shows significantly less brain exposure. Thus, dictyostatin
merits further investigation as a potential tauopathy therapeutic.
Blood−brain barrier; discodermolide; dictyostatin; microtubule; pharmacokinetics; tauopathy
A hallmark pathological feature of the Alzheimer’s
(AD) brain is the presence of senile plaques, which comprise amyloid
β (Aβ) peptides that are derived from the amyloid precursor
protein (APP). The plaque-containing AD brain is thought to be under
oxidative stress, as evidenced by increased lipid oxidation products
that include isoprostane-F2αIII (iPF2αIII). IPF2αIII
can bind to
and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor
activation causes increased Aβ production through enhancement
of APP mRNA stability. Moreover, TP receptor antagonists have been
shown to block iPF2αIII-induced increases of Aβ
secretion. Thus, the TP receptor may be a potential drug target for
AD therapy. However, here we show that existing TP receptor antagonists
have poor blood-brain barrier (BBB) permeability, likely due to the
presence of a carboxylic acid moiety that is believed to be important
for receptor interaction, but which may hamper passive diffusion across
the BBB. We now report selected analogues of a known tetrahydronaphthalene
TP receptor antagonist, wherein the carboxylic acid moiety has been
replaced by heterocyclic bioisosteres. These heterocyclic analogues
retained relatively high affinity for the mouse and human TP receptors,
and, unlike the parent carboxylic acid compound, several examples
freely diffused across the BBB into the brain upon administration
to mice. These results reveal that brain-penetrant tetrahydronaphthalene
TP receptor antagonists can be developed by substituting the carboxylic
acid moiety with a suitable nonacidic bioisostere. Compounds of this
type hold promise as potential lead structures to develop drug candidates
for the treatment of AD.
Alzheimer’s disease; amyloid precursor protein; antagonist; blood-brain barrier; plaques; thromboxane receptor
The microtubule (MT)-associated protein tau, which is highly expressed in the axons of neurons, is an endogenous MT-stabilizing agent that plays an important role in the axonal transport. Loss of MT-stabilizing tau function, caused by misfolding, hyperphosphorylation and sequestration of tau into insoluble aggregates, leads to axonal transport deficits with neuropathological consequences. Several in vitro and preclinical in vivo studies have shown that MT-stabilizing drugs can be utilized to compensate for the loss of tau function and to maintain/restore an effective axonal transport. These findings indicate that MT-stabilizing compounds hold considerable promise for the treatment of Alzheimer disease and related tauopathies. The present article provides a synopsis of the key findings demonstrating the therapeutic potential of MT-stabilizing drugs in the context of neurodegenerative tauopathies, as well as an overview of the different classes of MT-stabilizing compounds.
Neurons within the brains of those with AD (Alzheimer’s disease) and related neurodegenerative disorders, collectively termed ‘tauopathies’, contain fibrillar inclusions composed of hyperphosphorylated tau protein. Tau is normally enriched in axons, where it binds and stabilizes MTs (microtubules). Tau hyperphosphorylation and aggregation probably result in reduced MT binding that could affect axonal transport and neuronal function. A possible therapeutic strategy to overcome a loss of tau function in tauopathies is administration of MT-stabilizing agents, such as those used in the treatment of cancer. However, these drugs elicit severe side effects, and most existing MT-stabilizing compounds have poor BBB (blood–brain barrier) permeability, which renders them unsuitable for tauopathy treatment. We identified EpoD (epothilone D) as a brain-penetrant MT-stabilizing agent with preferred pharmacokinetic and pharmacodynamic properties. EpoD was evaluated for its ability to compensate for tau loss-of-function in an established Tg (transgenic) mouse model, using both preventative and interventional dosing paradigms. EpoD at doses much lower than previously used in human cancer patients caused improved axonal MT density and decreased axonal dystrophy in the tau Tg mice, leading to an alleviation of cognitive deficits. Moreover, EpoD reduced the extent of tau pathology in aged tau Tg mice. Importantly, no adverse side effects were observed in the EpoD-treated mice. These results suggest that EpoD might be a viable drug candidate for the treatment of AD and related tauopathies.
Alzheimer’s disease; axon; microtubule; tauopathy; therapeutic agent
The data reported in the Technical Comments by Fitz et al., Price et al., Tesseur et al., and Veeraraghavalu et al. replicate and validate our central conclusion that bexarotene stimulates the clearance of soluble β-amyloid peptides and results in the reversal of behavioral deficits in mouse models of Alzheimer’s disease (AD). The basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden is unexplained. However, we concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.
Alzheimer’s disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator–activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.
Cyclopentane-1,3-diones are known to exhibit pKa values typically in the range of carboxylic acids. To explore the potential of the cyclopentane-1,3-dione unit as a carboxylic acid isostere, the physical-chemical properties of representative congeners were examined and compared with similar derivatives bearing carboxylic acid or tetrazole residues. These studies suggested that cyclopentane-1,3-diones may effectively substitute for the carboxylic acid functional group. To demonstrate the use of the cyclopentane-1,3-dione isostere in drug-design, derivatives of a known thromboxane-A2 prostanoid (TP) receptor antagonist, 3-(3-(2-(4-chlorophenylsulfonamido)ethyl)-phenyl)propanoic acid (12), were synthesized and evaluated in both functional and radioligand-binding assays. A series of mono- and di-substituted cyclopentane-1,3-dione derivatives (41–45) were identified that exhibit nM IC50 and Kd values similar to 12. Collectively, these studies demonstrate that the cyclopentane-1,3-dione moiety comprises a novel isostere of the carboxylic acid functional group. Given the combination of the relatively strong acidity, tunable lipophilicity, and versatility of the structure, the cyclopentane-1,3-dione moiety may constitute a valuable addition to the palette of carboxylic acid isosteres.
isostere; bio-isostere; TP receptor; antagonist; cyclopentane-1,3-dione
Since over-activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in Alzheimer’s disease (AD), dysregulation of stress neuromediators may play a mechanistic role in the pathophysiology of AD. However, the effects of stress on tau phosphorylation are poorly understood and the relationship between corticosterone and corticotropin-releasing factor (CRF) on both Aβ and tau pathology remain unclear. Therefore, we first established a model of chronic stress which exacerbates Aβ accumulation in Tg2576 mice and then extended this stress paradigm to a tau transgenic mouse model with the P301S mutation (PS19) which displays tau hyperphosphorylation, insoluble tau inclusions and neurodegeneration. We show for the first time that both Tg2576 and PS19 mice demonstrate a heightened HPA stress profile in the unstressed state. In Tg2576 mice, one month of restraint/isolation (RI) stress increased Aβ levels, suppressed microglial activation, and worsened spatial and fear memory compared to non-stressed mice. In PS19 mice, RI stress promoted tau hyperphosphorylation, insoluble tau aggregation, neurodegeneration and fear-memory impairments. These effects were not mimicked by chronic corticosterone administration but were prevented by pre-stress administration of a CRF receptor type 1 (CRF1) antagonist. The role for a CRF1-dependent mechanism was further supported by the finding that mice over-expressing CRF had increased hyperphosphorylated tau compared to wildtype littermates. Together, these results implicate HPA dysregulation in AD neuropathogenesis and suggest that prolonged stress may increase Aβ and tau hyperphosphorylation. These studies also implicate CRF in AD pathophysiology and suggest that pharmacological manipulation of this neuropeptide may be a potential therapeutic strategy for AD.
stress; corticosterone; corticotropin-releasing factor; hypothalamic-pituitary-adrenal axis; Alzheimer’s disease; β-amyloid; tau
A hallmark of the Alzheimer disease (AD) brain is the presence of inclusions within neurons that are comprised of fibrils formed from the microtubule-stabilizing protein tau. The formation of misfolded multimeric tau species is believed to contribute to the progressive neuron loss and cognitive impairments of AD. Moreover, mutations in tau have been shown to cause a form of frontotemporal lobar degeneration in which tau neuronal inclusions observed in the brain are similar to those seen in AD. Here we review the more compelling strategies that are designed to reduce the contribution of misfolded tau to AD neuropathology, including those directed at correcting a possible loss of tau function resulting from sequestration of cellular tau and to minimizing possible gain-of-function toxicities caused by multimeric tau species. Finally, we discuss the challenges and potential benefits of tau-directed drug discovery programs.
Neurodegeneration in Alzheimer disease is likely caused by misfolded, multimeric tau. Therapeutic strategies have focused on overcoming tau loss-of-function and reducing levels of potentially toxic tau species.
The microtubule-associated protein tau forms insoluble filaments that deposit as neurofibrillary tangles (NFTs) in the brains of those with Alzheimer’s disease (AD) and other related neurodegenerative disorders. The presence of both NFTs and amyloid β (Aβ)-containing senile plaques within the brain is required to confirm the diagnosis of AD. However, the demonstration that familial AD can be caused by mutations that result in increased Aβ production has resulted in AD drug discovery strategies that are largely focused on reducing brain Aβ levels, with substantially less emphasis on tau-directed approaches. This trend may be changing, as there are an increasing number of research programs that are exploring ways to reduce NFTs in AD and related tauopathies. We briefly review recent advances in tau-based drug discovery, with an emphasis on the identification of compounds that inhibit the assembly of tau into multimers and fibrils.
Agents capable of preventing the misfolding and sequestration of the microtubule-stabilizing protein tau into insoluble fibrillar aggregates hold considerable promise for the prevention and/or treatment of neurodegenerative tauopathies such as Alzheimer’s disease. Because tauopathies are characterized by amyloidosis that is restricted to the central nervous system (CNS), plausible candidate compounds for in vivo evaluation must both prevent tau fibrillization and achieve significant brain levels. Recently, we reported the discovery of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors and now describe a series of new analogues that are both effective inhibitors of tau fibrillization and display significant brain-to-plasma exposure ratios after administration to mice. Further, two of the most promising examples, 15 and 16, were found to reach significant brain exposure levels following oral administration. Taken together, these results suggest that examples from the ATPZ class hold promise as candidates for in vivo efficacy studies in animal models of neurodegenerative tauopathies.
aminothienopyridazine; tauopathy; Alzheimer’s disease; amyloid; tau-aggregation inhibitor
The assembly of tau proteins into paired helical filaments, the building blocks of neurofibrillary tangles, is linked to neurodegeneration in Alzheimer’s disease and related tauopathies. A greater understanding of this assembly process could identify targets for the discovery of drugs to treat Alzheimer’s disease and related disorders. Using recombinant human tau, we have delineated events leading to the conversion of normal soluble tau into tau fibrils
Atomic force microscopy and transmission electron microscopy methodologies were utilized to determine the structure of tau assemblies that formed when soluble tau was incubated with heparin for increasing lengths of time.
Tau initially oligomerizes into spherical nucleation units of 18–21 nm diameter that appear to assemble linearly into nascent fibrils. Among the earliest tau fibrils are species that resemble a string of beads formed by linearly aligned spheres that with time seem to coalesce to form straight and twisted ribbon-like filaments, as well as paired-helical filaments similar to those found in human tauopathies. An analysis of fibril cross-sections at later incubation times revealed three fundamental axial structural features.
By monitoring tau fibrillization, we show that different tau filament morphologies co-exist. Temporal changes in the predominant tau structural species suggest that tau fibrillization involves the generation of structural intermediates, resulting in the formation of tau fibrils with verisimilitude to their authentic human counterparts.
Alzheimer’s disease; tauopathy; amyloid; tangles; neurodegeneration
Neuronal inclusions comprised of the microtubule-associated protein tau are found in a number of neurodegenerative diseases, commonly known as tauopathies. In Alzheimer's disease, the most prevalent tauopathy, misfolded tau is probably a key pathological agent. The recent failure of Aβ-targeted therapeutics in Phase III clinical trials suggests that it is timely and prudent to consider alternative drug discovery strategies for Alzheimer's disease. Here we focus on those directed at reducing misfolded tau and compensating for the loss of normal tau function.
The discovery that mutations within the tau gene lead to frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) provided direct evidence that tau alterations can lead to neurodegenerative disease. While the presence of tau fibrils and tangles is a common feature of all tauopathies, including Alzheimer’s disease (AD), data are emerging from biochemical, cell-based and transgenic mouse studies which suggest that a pre-fibrillar form of pathological tau may play a key role in eliciting central nervous system (CNS) neurodegeneration and behavioral impairments. Herein we review recent findings that implicate diffusible tau pathology in the onset of neurodegeneration, and discuss the implications of these findings as they relate to tau tangles and possible therapeutic strategies for the treatment of AD and related tauopathies.
Fibrils; Neurodegeneration; Oligomers; Tangles; Tau; Transgenic
TNFα is a pro-inflammatory cytokine that is elevated in Alzheimer’s disease (AD) brains. Since TNFα is released from cell membranes by the TNFα converting enzyme (TACE), inhibition of TACE has the potential to mitigate TNFα effects in AD brain. TACE also cleaves amyloid precursor protein (APP) and generates sAPPα, precluding the formation of potentially harmful Aβ peptides by β-site APP cleaving enzymes (BACE). Hence, the anti-inflammatory benefits of TACE inhibition might be offset by an increase in Aβ. We have examined the effects of the highly selective TACE inhibitor, BMS-561392, on APP processing in vitro and in vivo. In CHO cells expressing APP, BMS-561392 significantly reduced secretion of sAPPα without a corresponding increase in Aβ production. Conversely, a BACE inhibitor decreased sAPPβ and Aβ peptides with no change in the secretion of sAPPα. These data indicate an absence of TACE and BACE competition for the APP substrate. Despite this, we observed competition for APP when TACE activity was enhanced via phorbol ester treatment or if APP was modified such that it was retained within the trans Golgi network (TGN). These results suggest that BACE and TACE share a common TGN localization, but under normal conditions do not compete for APP. To confirm this finding in vivo, BMS-561392 was infused into the brains of Tg2576 and wild-type mice. While decreased brain sAPPα levels were observed, steady-state Aβ levels were not significantly changed. Accordingly, it is possible that TACE inhibitors could reduce TNFα levels without increasing Aβ levels within the AD brain.
Alzheimer’s disease; amyloid-beta; inflammation; neuroinflammation; tumor necrosis factor; TNFα