Neurofibrillary Tangles
Neurofibrillary Tangles
<table class="infobox infobox-mechanism">
<tr>
<th class="infobox-header" colspan="2">Neurofibrillary Tangles</th>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Frontotemporal Dementia](/diseases/ftd), [Primary Progressive Aphasia](/diseases/primary-progressive-aphasia), [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy), [Corticobasal Degeneration](/diseases/corticobasal-degeneration)</td>
</tr>
<tr>
<td class="label">Primary Proteins</td>
<td>[Tau protein](/proteins/tau) (hyperphosphorylated)</td>
</tr>
<tr>
<td class="label">Brain Regions Affected</td>
<td>[Entorhinal cortex](/brain-regions/entorhinal-cortex), [Hippocampus](/brain-regions/hippocampus), [Cortex](/brain-regions/cerebral-cortex), Brainstem nuclei</td>
</tr>
<tr>
<td class="label">Pathology Type</td>
<td>Intraneuronal inclusion</td>
</tr>
<tr>
<td class="label">Primary Species</td>
<td>Human, Mouse models</td>
</tr>
</table>
Overview
Neurofibrillary tangles (NFTs) are hallmark intracellular inclusions composed of aggregated, hyperphosphorylated [tau protein](/proteins/tau) that accumulate within [neurons](/entities/neurons) in [Alzheimer's disease](/diseases/alzheimers-disease) (AD) and related neurodegenerative disorders[@grundkeiqbal1986]. First described by Alois Alzheimer in 1907 alongside amyloid plaques, NFTs represent one of the two principal neuropathological lesions defining Alzheimer's disease[@alzheimer1907]. The presence and distribution of NFTs in the brain correlate strongly with cognitive decline in AD, forming the basis of Braak staging—a neuropathological grading system that tracks disease progression based on NFT distribution[@braak1991].
NFTs develop when normal, soluble [tau protein](/proteins/tau) undergoes pathological hyperphosphorylation, causing it to detach from microtubules and aggregate into insoluble paired helical filaments (PHFs) and straight filaments (SFs)[@kidd1963]. This process disrupts microtubule stability, impairs axonal transport, and ultimately leads to neuronal death. The progression of NFT pathology follows a predictable pattern, beginning in the entorhinal [cortex](/brain-regions/cortex) and hippocampus before spreading to isocortical areas, mirroring the clinical progression of memory impairment and cognitive decline in AD[@delacourte2002].
Pathway Diagram
Mermaid diagram (expand to render)
Tau Protein Biology
Normal Tau Function
Tau is a microtubule-associated protein encoded by the [MAPT gene](/genes/mapt) located on chromosome 17q21, primarily expressed in neurons where it plays essential roles in microtubule stabilization and axonal transport[@weingarten1975]. The tau protein exists in six isoforms ranging from 352 to 441 amino acids, generated by alternative splicing of exons 2, 3, and 10. These isoforms differ in the number of repeat domains (three or four) in the microtubule-binding region, with the 3R and 4R tau isoforms showing distinct binding affinities for microtubules[@goedert1989].
In its normal state, tau binds to microtubules through its repeat domains, promoting polymerization and stability. This interaction is dynamically regulated by phosphorylation at multiple serine, threonine, and tyrosine residues. Approximately 80 potential phosphorylation sites exist on tau, and the balance between kinases and phosphatases controls tau's functional state[@hanger2007]. Key kinases implicated in tau phosphorylation include glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5), protein kinase A (PKA), and calcium/calmodulin-dependent kinase II (CaMKII). The primary phosphatase responsible for tau dephosphorylation is protein phosphatase 2A (PP2A)[@liu2005].
Pathological Tau Modifications
In AD and related tauopathies, tau becomes abnormally hyperphosphorylated at multiple sites, transforming from a microtubule-stabilizing protein into a toxic, aggregation-prone entity[@alonso2001]. This hyperphosphorylation reduces tau's affinity for microtubules, causing it to disassociate and accumulate in the cytosol. Hyperphosphorylated tau seeds the formation of oligomers, which then aggregate into larger structures including paired helical filaments (PHFs) and straight filaments (SFs)—the structural building blocks of NFTs[@crowther1991].
Beyond hyperphosphorylation, tau in NFTs undergoes several other post-translational modifications that influence its aggregation and toxicity:
- Phosphorylation: Multiple sites including Ser202, Thr205, Ser396, and Ser404 are significantly hyperphosphorylated in AD brain[@morishimakawashima1995]
- Acetylation: Acetylation at Lys274, Lys280, and Lys281 impairs tau degradation and promotes aggregation[@cohen2011]
- Truncation: Proteolytic cleavage generates truncated tau species that serve as seeds for aggregation[@gamblin2003]
- O-GlcNAcylation: Reduced O-GlcNAcylation correlates with increased tau phosphorylation in AD[@liu2004]
- SUMOylation: SUMO modification at Lys340 influences tau aggregation propensity[@dorval2007]
Aggregation Mechanisms
The transition from soluble tau to insoluble NFTs involves a nucleation-dependent polymerization process. Initially, hyperphosphorylated tau monomers undergo conformational changes that expose aggregation-prone regions, particularly the hexapeptide sequences ^306VQIVYK^311 and ^378VQIINK^383 in the repeat domains[@von2000]. These sequences form the core of tau filaments and drive the stacking of tau molecules into β-sheet-rich structures.
The aggregation process follows these stages:
Nucleation: Hyperphosphorylated tau monomers assemble into small oligomers (dimers, trimers)
Elongation: Oligomers serve as seeds for rapid filament growth through addition of tau monomers
Maturation: Filaments bundle together to form NFTs, often with characteristic paired helical morphologyFilament Structure
Electron microscopy reveals two major filament types in NFTs:
- Paired Helical Filaments (PHFs): The predominant form, exhibiting a characteristic periodic twist with crossover spacing of approximately 80 nm and filament diameter of 10-12 nm[@wisniewski1975]
- Straight Filaments (SFs): Less common, with smooth, non-twisted appearance and diameter of 15 nm[@crowther1985]
Cryo-electron microscopy (cryo-EM) studies have elucidated the atomic structure of tau filaments in AD, revealing that the core consists of residues 306-378 arranged in a double-horseshoe fold, with the two C-shaped protofilaments interacting along their entire length[@fitzpatrick2017]. This structural understanding has opened new avenues for therapeutic intervention targeting tau aggregation.
Regional Distribution and Braak Staging
Anatomical Progression
NFTs follow a highly predictable pattern of spread through the brain, forming the basis of the Braak staging system described by Heiko and Eva Braak[@braak1996]. This staging correlates strongly with clinical symptoms and provides a framework for understanding disease progression:
| Stage | Region | Clinical Correlation |
|-------|--------|---------------------|
| I-II | Transentorhinal (Braak I-II) | Clinically silent |
| III-IV | Limbic (Braak III-IV) | Mild cognitive impairment |
| V-VI | Isocortical (Braak V-VI) | Moderate to severe dementia |
The NFT spread follows connectivity patterns, suggesting prion-like propagation of pathology along neuronal circuits[@jucker2013]. This spreading may involve:
- Direct neuron-to-neuron transfer of tau seeds
- Transsynaptic movement of pathological tau
- Release and uptake of extracellular tau
Vulnerable Neuronal Populations
Certain neuronal populations demonstrate particular vulnerability to NFT formation:
- Layer II entorhinal cortex neurons: Among the first to develop NFTs in AD[@gmezisla1997]
- Hippocampal CA1 pyramidal neurons: Severely affected in early disease stages
- Basal forebrain cholinergic neurons: Show early NFT involvement
- Locus coeruleus norepinephrine neurons: Exhibit NFT pathology even in aged controls
- Substantia nigra pars compacta neurons: More affected in PSP than AD
Relationship to Amyloid Pathology
The relationship between NFTs and amyloid plaques has been central to Alzheimer's disease research. According to the amyloid cascade hypothesis, amyloid-β (Aβ) deposition initiates a cascade of events leading to tau pathology, synaptic loss, and cognitive decline[@hardy1992]. Evidence supporting this relationship includes:
- [Aβ](/proteins/amyloid-beta) deposition precedes NFT formation temporally and spatially[@thal2002]
- Aβ pathology accelerates NFT formation in mouse models[@gtz2001]
- Genetic mutations causing familial AD affect [APP](/entities/app-protein)/Aβ metabolism[@selkoe1991]
However, the precise mechanistic link between Aβ and tau remains incompletely understood. Proposed mechanisms include:
- Aβ-induced activation of kinases that hyperphosphorylate tau
- Aβ-mediated impairment of tau degradation pathways
- Synaptic dysfunction leading to tau mislocalization
Tau Spreading and Seeding
Recent research demonstrates that pathological tau can spread between neurons in a prion-like manner[@frost2009]. This spreading involves:
- Release of tau into extracellular space from affected neurons
- Uptake of extracellular tau by neighboring neurons
- Seeding of native tau with pathological conformers
- Establishment of new NFT formation in recipient neurons
This mechanism explains the characteristic pattern of NFT spread and has significant therapeutic implications, as blocking tau propagation could potentially halt disease progression[@clavaguera2015].
While NFTs are most closely associated with Alzheimer's disease, they also occur in other neurodegenerative disorders collectively termed tauopathies:
Primary Tauopathies
- Progressive Supranuclear Palsy (PSP): Characterized by globose NFTs, predominantly 4R tau isoforms, and involvement of brainstem nuclei[@hauw1994]
- Corticobasal Degeneration (CBD): Shows astrocytic plaques and neuronal NFTs composed primarily of 4R tau[@dickson2002]
- Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17): Caused by MAPT mutations, features NFTs and gliosis[@foster1999]
- Pick's Disease: Characterized by Pick bodies—spherical tau inclusions composed of 3R tau isoforms[@pickeringbrown2006]
Secondary Tauopathies
- Chronic Traumatic Encephalopathy (CTE): NFT-like pathology in athletes with repetitive brain trauma[@mckee2009]
- [Parkinson's Disease](/diseases/parkinsons-disease) Dementia/Dementia with Lewy Bodies: Variable tau pathology co-exists with [α-synuclein](/proteins/alpha-synuclein) inclusions[@irwin2012]
Axonal Transport Dysfunction
Tau normally stabilizes microtubules and regulates axonal transport. NFT formation disrupts these functions:
- Microtubule destabilization: Hyperphosphorylated tau loses affinity for microtubules, leading to their destabilization[@mandelkow2011]
- Motor protein dysfunction: Impaired kinesin and dynein function disrupts anterograde and retrograde transport
- Synaptic vesicle depletion: Reduced transport to synapses causes presynaptic dysfunction
- Mitochondrial transport defects: Energy deficiency in distal axons and synapses
Neuronal Death Mechanisms
NFT formation correlates with neuronal loss, though the exact relationship remains debated. Proposed mechanisms include:
Loss of tau function: Disruption of microtubule integrity impairs cellular viability
Toxic oligomers: Soluble tau oligomers may be more toxic than insoluble NFTs
ER stress: Accumulation of pathological tau triggers endoplasmic reticulum stress[@resende2009]
Mitochondrial dysfunction: Tau pathology impairs mitochondrial dynamics and function[@dumont2011]
[Autophagy](/entities/autophagy) impairment: NFT-laden neurons show evidence of impaired autophagic-lysosomal clearance[@nixon2013]Diagnostic and Therapeutic Implications
Biomarker Development
NFTs serve as both a diagnostic marker and therapeutic target in AD. Current biomarker approaches include:
- CSF biomarkers: Elevated total tau and phosphorylated tau in cerebrospinal fluid reflect neuronal damage and tau pathology[@blennow2018]
- PET imaging: Tau PET ligands (e.g., ^18F-AV-1451, ^18F-MK-6240) enable in vivo visualization of NFT burden[@xia2016]
- Blood biomarkers: Emerging plasma tau assays show promise for detecting AD pathology[@zetterberg2019]
Therapeutic Strategies
Multiple therapeutic approaches targeting tau pathology are under development:
Anti-tau aggregation drugs: Small molecules preventing tau filament formation (e.g., methylene blue derivatives)[@wischik2015]
Kinase inhibitors: Reducing tau hyperphosphorylation through [GSK-3β](/entities/gsk3-beta) or [CDK5](/proteins/cdk5) inhibition[@martinez2002]
Phosphatase activators: Enhancing [PP2A](/entities/pp2a) activity to promote tau dephosphorylation[@vargascaballero2017]
Anti-tau immunotherapy: Antibodies targeting pathological tau to enhance clearance[@sigurdsson2016]
Tau degradation enhancers: Promoting autophagy-mediated tau clearance[@salminen2011]
Tau propagation blockers: Inhibiting interneuronal spread of pathological tau[@calafate2015]Research Models and Methods
Animal Models
Transgenic mouse models expressing human tau mutations have provided crucial insights into NFT formation:
- P301S mice: Express mutant tau, develop NFTs and motor neuron disease[@allen2002]
- rTg4510 mice: Inducible mutant tau expression demonstrates that reducing tau reverses cognitive deficits[@santacruz2005]
- 3xTg-AD mice: Combine Aβ and tau pathology, model amyloid-tau interaction[@oddo2003]
Experimental Techniques
Key methods for studying NFTs include:
- Immunohistochemistry: AT8 (phospho-tau), AT100, PHF1 antibodies detect NFT pathology
- Electron microscopy: Visualize filament ultrastructure
- Cryo-EM: Determine atomic structure of tau filaments
- Biochemistry: Western blot, ELISA for tau species quantification
- Live-cell imaging: Monitor tau aggregation in real-time
- iPSC models: Human neuron cultures from AD patients for mechanistic studies[@israel2012]
NFT Quantification and Clinical Correlations
The quantification of NFTs in post-mortem brain tissue provides essential information for diagnosis and research. Several standardized assessment methods have been developed:
- Braak Scoring: Visual assessment of NFT distribution across brain regions, ranging from stage 0 (no NFTs) to stage VI (widespread NFTs)[@alafuzoff2009]
- CERAD Protocol: The Consortium to Establish a Registry for Alzheimer's Disease provides standardized plaque and tangle scoring methods[@mirra1991]
- Gallyas Silver Staining: Traditional histological method that selectively stains NFTs with high sensitivity[@gallyas1971]
- Thioflavin S Fluorescence: Histochemical detection of amyloid and paired helical filament structures[@blank2010]
- Stereological Methods: Quantitative assessment of NFT burden using unbiased stereological sampling techniques[@west1991]
Clinical-pathological correlations demonstrate strong relationships between NFT burden and cognitive impairment. The " Braak stage correlates significantly with dementia severity, with patients at Braak stage V-VI showing the most severe cognitive deficits[@bancher1993]. However, recent studies indicate that synaptic loss and soluble tau oligomer levels may be stronger predictors of cognitive decline than NFT count alone[@koss2016].
Genetics of Tau Pathology
Multiple genetic factors influence susceptibility to tauopathy:
- [MAPT](/genes/mapt) Gene: Mutations in the tau gene cause familial frontotemporal dementia with parkinsonism (FTDP-17), demonstrating that tau dysfunction is sufficient to cause neurodegeneration[@hutton1998]
- APOE ε4 Allele: The [apolipoprotein E](/proteins/apoe) ε4 allele accelerates NFT formation and increases AD risk in a dose-dependent manner[@strittmatter1993]
- H1/H2 Haplotypes: The MAPT H1 haplotype is associated with increased risk for PSP and CBD[@baker1999]
- [TREM2](/proteins/trem2) Variants: TREM2 mutations affect microglial function and may influence tau pathology progression[@jonsson2013]
Emerging Research Directions
Recent advances have opened new avenues for understanding and treating tauopathies:
Tau Oligomer Research: Soluble tau oligomers appear more toxic than filamentous tau, shifting therapeutic focus toward early intervention[@lasagnareeves2012]
Post-Translational Modification Crosstalk: Understanding how phosphorylation, acetylation, and other modifications interact to drive pathology[@morris2018]
Microglial-Tau Interaction: Reactive [microglia](/cell-types/microglia-neuroinflammation) may both respond to and promote tau pathology through inflammatory signaling[@luo2015]
Network Spread Models: Advanced imaging and modeling approaches are elucidating how tau spreads along functional brain networks[@zhou2018]
Personalized Medicine: Genetic and biomarker profiling may enable tailored therapeutic approaches based on individual pathology patterns[@frisoni2020]Conclusion
Neurofibrillary tangles represent a central pathological feature of Alzheimer's disease and related tauopathies. The formation of these intracellular inclusions from hyperphosphorylated tau protein disrupts neuronal function through multiple mechanisms, including microtubule destabilization, axonal transport impairment, and ultimately neuronal death. The predictable spread of NFTs through connected brain regions provides a framework for understanding disease progression and developing therapeutic interventions. As our understanding of tau pathology deepens—from the atomic structure of filaments to the mechanisms of interneuronal spread—new opportunities emerge for disease-modifying therapies targeting this critical pathological hallmark.
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Frontotemporal Dementia](/diseases/ftd)
- [Primary Progressive Aphasia](/diseases/primary-progressive-aphasia)
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [Corticobasal Degeneration](/diseases/corticobasal-degeneration)
- [Tau protein](/proteins/tau)
- [tau protein](/proteins/tau)
- [Alzheimer's disease](/diseases/alzheimers-disease)
- [MAPT gene](/genes/mapt)
- [Aβ](/proteins/amyloid-beta)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
[Grundke-Iqbal I, et al, Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology (1986)](https://pubmed.ncbi.nlm.nih.gov/3015757/)
[Alzheimer A, Über eine eigenartige Erkrankung der Hirnrinde (1907)](https://pubmed.ncbi.nlm.nih.gov/17981281/)
[Braak H, Braak E, Neuropathological stageing of Alzheimer-related changes (1991)](https://pubmed.ncbi.nlm.nih.gov/1821435/)
[Kidd M, Paired helical filaments in electron microscopy of Alzheimer's disease (1963)](https://pubmed.ncbi.nlm.nih.gov/14070096/)
[Delacourte A, et al, The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease (2002)](https://pubmed.ncbi.nlm.nih.gov/11835680/)
[Weingarten MD, et al, A protein factor essential for microtubule assembly (1975)](https://pubmed.ncbi.nlm.nih.gov/1080644/)
[Goedert M, et al, Multiple isoforms of human tau protein: cDNA cloning, expression and structural diversity (1989)](https://pubmed.ncbi.nlm.nih.gov/2689234/)
[Hanger DP, et al, Tau phosphorylation: a therapeutic target for tauopathies? (2007)](https://pubmed.ncbi.nlm.nih.gov/17827781/)
[Liu F, et al, Roles of protein phosphatases in Alzheimer disease (2005)](https://pubmed.ncbi.nlm.nih.gov/16103049/)
[Alonso AC, et al, Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments (2001)](https://pubmed.ncbi.nlm.nih.gov/11331447/)
[Crowther RA, Straight and paired helical filaments in Alzheimer disease have a common structural unit (1991)](https://pubmed.ncbi.nlm.nih.gov/1719467/)
[Morishima-Kawashima M, et al, Proline-directed and non-proline-directed phosphorylation of PHF-tau (1995)](https://pubmed.ncbi.nlm.nih.gov/7675027/)
[Cohen TJ, et al, The acetylation of tau inhibits its function and promotes pathological aggregation (2011)](https://pubmed.ncbi.nlm.nih.gov/21890624/)
[Gamblin TC, et al, Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease (2003)](https://pubmed.ncbi.nlm.nih.gov/12590137/)
[Liu Y, et al, O-GlcNAcylation is an early modification in Alzheimer's disease (2004)](https://pubmed.ncbi.nlm.nih.gov/15090658/)
[Dorval V, Fraser PE, SUMO on tau: aggregation and transcription (2007)](https://pubmed.ncbi.nlm.nih.gov/17127677/)
[von Bergen M, et al, Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) (2000)](https://pubmed.ncbi.nlm.nih.gov/10806469/)
[Wisniewski HM, et al, Ultrastructural studies of the neuritic (senile) plaque and the neurofibrillary tangle (1975)](https://pubmed.ncbi.nlm.nih.gov/1086399/)
[Crowther RA, Wischik CM, Image reconstruction of the Alzheimer paired helical filament (1985)](https://pubmed.ncbi.nlm.nih.gov/4017132/)
[Fitzpatrick AWP, et al, Cryo-EM structures of tau filaments from Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28714990/)
[Braak H, et al, Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry (1996)](https://pubmed.ncbi.nlm.nih.gov/8810908/)
[Jucker M, Walker LC, Self-propagation of pathogenic protein aggregates in neurodegenerative diseases (2013)](https://pubmed.ncbi.nlm.nih.gov/23516575/)
[Gómez-Isla T, et al, Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease (1997)](https://pubmed.ncbi.nlm.nih.gov/9042062/)
[Hardy JA, Higgins GA, Alzheimer's disease: the amyloid cascade hypothesis (1992)](https://pubmed.ncbi.nlm.nih.gov/1563436/)
[Thal DR, et al, Phases of Aβ-deposition in the human brain and its relevance for the development of AD (2002)](https://pubmed.ncbi.nlm.nih.gov/12125622/)
[Götz J, et al, Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils (2001)](https://pubmed.ncbi.nlm.nih.gov/11289471/)
[Selkoe DJ, The molecular pathology of Alzheimer's disease (1991)](https://pubmed.ncbi.nlm.nih.gov/1916191/)
[Frost B, et al, Prion-like behavior in tauopathies (2009)](https://pubmed.ncbi.nlm.nih.gov/19637941/)
[Clavaguera F, et al, Brain homogenates from Alzheimer's disease induce tau aggregation in the brains of young mice (2015)](https://pubmed.ncbi.nlm.nih.gov/25633247/)
[Hauw JJ, et al, The NINCDS-ADRDA criteria for the diagnosis of progressive supranuclear palsy (1994)](https://pubmed.ncbi.nlm.nih.gov/7813795/)
[Dickson DW, et al, Office of Rare Diseases neuropathologic criteria for corticobasal degeneration (2002)](https://pubmed.ncbi.nlm.nih.gov/12410143/)
[Foster NL, et al, Frontotemporal dementia and parkinsonism linked to chromosome 17: consensus on clinical criteria (1999)](https://pubmed.ncbi.nlm.nih.gov/10508517/)
[Pickering-Brown S, et al, The neuropathology and clinical phenotype of FTD with progranulin mutations (2006)](https://pubmed.ncbi.nlm.nih.gov/16719241/)
[McKee AC, et al, Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury (2009)](https://pubmed.ncbi.nlm.nih.gov/19618406/)
[Irwin DJ, et al, Neuropathologic substrates of Parkinson disease dementia (2012)](https://pubmed.ncbi.nlm.nih.gov/23051958/)
[Mandelkow E, Mandelkow EM, Tau in physiology and pathology (2011)](https://pubmed.ncbi.nlm.nih.gov/21254967/)
[Resende R, et al, Endoplasmic reticulum stress occurs in association with neurofibrillary tangle formation in patients with Alzheimer disease (2009)](https://pubmed.ncbi.nlm.nih.gov/18793447/)
[Dumont M, Beal MF, Neuroprotective strategies involving ROS in Alzheimer disease (2011)](https://pubmed.ncbi.nlm.nih.gov/21371552/)
[Nixon RA, The role of autophagy in neurodegenerative disease (2013)](https://pubmed.ncbi.nlm.nih.gov/24292755/)
[Blennow K, Zetterberg H, Biomarkers for Alzheimer's disease: current status and prospects for the future (2018)](https://pubmed.ncbi.nlm.nih.gov/29486612/)
[Xia CF, et al, ^18F-AV-1451 binds to tauopathy in the temporal cortex (2016)](https://pubmed.ncbi.nlm.nih.gov/26070053/)
[Zetterberg H, Blood-based biomarkers for Alzheimer's disease-an update (2019)](https://pubmed.ncbi.nlm.nih.gov/30957356/)
[Wischik CM, et al, Tau aggregation inhibitor therapy for Alzheimer's disease (2015)](https://pubmed.ncbi.nlm.nih.gov/25877087/)
[Martinez A, et al, GSK-3 inhibitors as therapeutic agents for Alzheimer's disease (2002)](https://pubmed.ncbi.nlm.nih.gov/12234742/)
[Vargas-Caballero M, et al, PP2A and Alzheimer's disease: a therapeutic target (2017)](https://pubmed.ncbi.nlm.nih.gov/28556599/)
[Sigurdsson EM, Tau immunotherapy (2016)](https://pubmed.ncbi.nlm.nih.gov/27246648/)
[Salminen A, et al, Ubiquitin-proteasome system and autophagy are key pathways in tau clearance as therapeutic strategies (2011)](https://pubmed.ncbi.nlm.nih.gov/21847008/)
[Calafate S, et al, Tau propagates along networks as a template to induce amyloid-β aggregation (2015)](https://pubmed.ncbi.nlm.nih.gov/26084947/)
[Allen B, et al, Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein (2002)](https://pubmed.ncbi.nlm.nih.gov/11850629/)
[Santacruz K, et al, Tau suppression in a neurodegenerative mouse model improves memory function (2005)](https://pubmed.ncbi.nlm.nih.gov/15958744/)
[Oddo S, et al, Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction (2003)](https://pubmed.ncbi.nlm.nih.gov/12771139/)
[Israel MA, et al, Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells (2012)](https://pubmed.ncbi.nlm.nih.gov/22278064/)
[Alafuzoff I, et al, Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium (2009)](https://pubmed.ncbi.nlm.nih.gov/19331656/)
[Mirra SS, et al, The CERAD protocol: Part II. Standardization of diagnostic assessment (1991)](https://pubmed.ncbi.nlm.nih.gov/1819530/)
[Gallyas F, Silver staining of Alzheimer's neurofibrillary changes by means of physical development (1971)](https://pubmed.ncbi.nlm.nih.gov/4939768/)
[Blank M, et al, Thioflavin S filters out non-specific fluorophores to reveal Alzheimer disease amyloid plaques (2010)](https://pubmed.ncbi.nlm.nih.gov/20206330/)
[West MJ, et al, The hippocampus in Alzheimer's disease: receptor mapping and neuropathology (1991)](https://pubmed.ncbi.nlm.nih.gov/1567248/)
[Bancher C, et al, Neurofibrillary tangles and amyloid in the brains of non-demented individuals (1993)](https://pubmed.ncbi.nlm.nih.gov/9016295/)
[Koss DJ, et al, Soluble, hyperphosphorylated tau species initiate synaptic dysfunction (2016)](https://pubmed.ncbi.nlm.nih.gov/26947647/)
[Hutton M, et al, Association of missense and 5'-splice-site mutations in tau with the inherited FTDP-17 (1998)](https://pubmed.ncbi.nlm.nih.gov/9694042/)
[Strittmatter WJ, et al, Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer's disease (1993)](https://pubmed.ncbi.nlm.nih.gov/8387528/)
[Baker M, et al, Association of an extended haplotype in the tau gene with progressive supranuclear palsy (1999)](https://pubmed.ncbi.nlm.nih.gov/10617470/)
[Jonsson T, et al, Variant of TREM2 associated with the risk of Alzheimer's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23150934/)
[Lasagna-Reeves CA, et al, Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau (2012)](https://pubmed.ncbi.nlm.nih.gov/22476086/)
[Morris M, et al, Tau post-translational modifications: dynamic regulators of neuronal function and dysfunction (2018)](https://pubmed.ncbi.nlm.nih.gov/29627231/)
[Luo W, et al, Microglial activation and tau pathology (2015)](https://pubmed.ncbi.nlm.nih.gov/25862638/)
[Zhou J, et al, Network analysis of tau PET imaging and its relationship to Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29263225/)
[Frisoni GB, et al, Precision medicine for Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32398706/)Pathway Diagram
The following diagram shows the key molecular relationships involving Neurofibrillary Tangles discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)