Wikipedia

Primary age-related tauopathy

Primary age-related tauopathy (PART) is a neuropathological designation introduced in 2014 to describe the neurofibrillary tangles (NFT) that are commonly observed in the brains of normally aged and cognitively impaired individuals that can occur independently of the amyloid plaques of Alzheimer's disease (AD).[1][2] The term and diagnostic criteria for PART were developed by a large group of neuropathologists, spearheaded by Drs. John F. Crary (then at Columbia University Medical Center) and Peter T. Nelson (University of Kentucky).[3] Despite some controversy,[4][5] the term PART has been widely adopted, with the consensus criteria cited over 1130 times as of April 2023 according to Google Scholar.

At autopsy, the hallmark of PART is the presence of Alzheimer-type neurofibrillary tangles (NFTs) composed of abnormal tau protein in neurons in the medial temporal lobe, but no amyloid-beta (Aβ42) peptide accumulation in plaques.[2] This ultimately leads to neuronal death and brain atrophy.[6] 18% of Alzheimer neuropathological changes in cognitively normal and 5% of cognitively impaired elderly cases have been shown to display this pattern of degeneration.[7] Patients with severe PART typically exhibit mild cognitive impairment or an amnestic dementia.[2]

Diagnostics

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Neuropathological features

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Patients with PART display neurofibrillary tangles that are essentially identical to those occurring in mild to moderate-stage Alzheimer's disease and other tauopathies.[8] Amyloid pathology is sparse or absent in patients with PART.[2][7] If few senile plaques are found, Thal phase grading can be implemented to differentiate the pathology as either PART or AD.[7]

Clinical features

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Patients with PART can be cognitively normal, mildly cognitively impaired, or demented.[9][7] Specifically, higher stages of tangle burden (i.e. Braak III or IV) in PART have been found to be associated with more rapid decline on tasks involving episodic and semantic memory along with tests of processing speed and attention.[9] Braak state 0 is restricted to the cortex, state l-ll bound by transentorhinal region and it can progress into limbic region of the brain (stage lll-lV).[10] PART can be further categorized as symptomatic (cognitive impairment and dementia) and asymptomatic (no signs of dementia).[7][6] One current hypothesis suggests that PART related dementia could be infrequent in younger populations, but may show symptomatic onset within oldest old (people greater than 90 years old).[11] Given that the elderly represent a fast growing segment of the population worldwide, further research is needed to understand how PART related pathological process can manifest in specific clinical symptoms.

Furthermore, serological testing cannot be used to identify PART patients and MRI scans are the only current available diagnostic tools.[12]

Relationship to Alzheimer's disease

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Given the similarities in the pattern of neurofibrillary tangles in PART, some scientists have argued that they represent the same phenomenon.[13][14] However, others have argued that sufficient evidence exists to conclude that PART represents a pathological process.[15] Further more, Aβ42 presence in AD contributes to tau hyper phosphorylation and consequently its development into NFTs.[16][17] Aβ42 is absent in PART and due to several mechanisms underlying tau formation and maintenance, it would be necessary to separate PART from AD due to implications with respect to developing diagnostics and therapeutics.[2][18][19]

Genetics

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PART has been associated with microtubule association tau protein (MAPT) H1 haplotype and no association has been seen with APOE ε4, a gene strongly linked to AD.[2][8][19] Thus another piece of evidence supporting the hypothesis that PART represents a novel diagnostic category. Also transformation as a result of tau mutation into isoforms (3R and 4R) on chromosome 17 has been linked to Parkinson and frontotemporal dementia.[18] Transformation in tau gene on chromosome 17 can be linked to PART due to the fact that the tau protein analyzed from PART NFTs consist of 3R and 4R isoforms.[12] MAPT gene results in different tau protein isoforms due to splicing patterns of exon 10.[10]

Pathophysiology

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MRI, immunoblot and immunofluorescence tools have allowed researchers to identify and observe tau protein aggregation both intra and intercellullary as well as their interaction with other proteins.[2][7][18] Immunohistochemistry of brain autopsy of PART cases reveal that NFT's appear in the hippocampus area which is involved in memory formation.[2] Also development of specific tau tracers allows for positron emission tomography (PET) imaging allowing for both intracellular and extracellular observation of tau protein behaviours.[10]

Owing to these imaging and staining advancements, tau has been identified to be associated with microtubules in neuron cells.[20] Tau protein stabilize the microtubules and are involved in fast dendrite growth, retrograde and antegrade transport intracellularly and neuron maintenance.[20]

Tau protein is divided into three segments, i.e. N-terminal (regulated spacing of microtubules), C-terminal (microtubule polymerization), proline rich domain (kinase) and microtubule binding domain.[12] Tau in brain of patients with tauopathies is hyperphosphorylated which causes the tau protein to dissociate from the microtubule then aggregate in to β-plated sheet arrangement.[12] PART cases is due to tau protein isoforms (3 and 4 microtubule binding repeats) abnormal ration inneural cells resulting in their self assembling and accumulation resulting in NFT formation in brain.[12][17][18] Detachment of tau from microtubules causes the neuron to lose its ability to sustain its self and thus ultimately loses function.

Hyper-phosphorylation of tau protein was initially thought to be caused by Aβ42 but since PART cases generally lack senile plaques, other causes were investigated. One such cause was found to me the microtubule affinity-regulating kinase (MARK) since it is involved in tau phosphorylation and dephosphorylation.[18][19] Overexpression of MARK gene results in excessive tau phosphorylation and eventually NFT's formation.[18][19] It is suspected that at a threonine (Thr175 ), kinases such as GSK3β and MARK hyper-phosphorylate the mutant tau protein residue.[20] Also researcher have linked to NFT survive (mutant tau protein maintenance) to heat shock protein 90 (HSP90) since HSP90 performs such function in cancer cells and its inhibition resulted in elimination of tau aggregates in vivo.[18]

Recent finding's on tau regulation has revealed small non coding RNAs bind to recognition motifs on mRNAs and silence their expression through post-translational regulation.[21] MiRNA-219 binds to tau mRNA and represses tau protein synthesis since in fly model brain, over expression of miRNA-219 reduced the tau protein accumulation.[21]

Treatment

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These options listed below have not been yet linked or specified for PART treatment since the disease is yet to gain acceptance as a unique abnormality case by the medical community. Thus the treatments represent possible future options as per the research and finding in the medical literature.

HSP90 Targets

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PU-DZ8 can pass the blood brain barrier and act on HSP90 to inhibit it.[18]

Small molecule inhibitors

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Staurosporine, Methylene blue and other kinase inhibitors can pass the blood brain barrier and inhibit MARK which consequently down regulation tau protein hyper-phosphorylation and ultimately its detachment from microtubules.[19]

References

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  1. ^ "Researchers identify new neurological disorder linked to Alzheimer's" Medical news today, November 14, 2014
  2. ^ a b c d e f g h Crary, John F.; Trojanowski, John Q.; Schneider, Julie A.; Abisambra, Jose F.; Abner, Erin L.; Alafuzoff, Irina; Arnold, Steven E.; Attems, Johannes; Beach, Thomas G. (2014-12-01). "Primary age-related tauopathy (PART): a common pathology associated with human aging". Acta Neuropathologica. 128 (6): 755–766. doi:10.1007/s00401-014-1349-0. ISSN 0001-6322. PMC 4257842. PMID 25348064.
  3. ^ Crary, John F.; Trojanowski, John Q.; Schneider, Julie A.; Abisambra, Jose F.; Abner, Erin L.; Alafuzoff, Irina; Arnold, Steven E.; Attems, Johannes; Beach, Thomas G. (2014-12-01). "Primary age-related tauopathy (PART): a common pathology associated with human aging". Acta Neuropathologica. 128 (6): 755–766. doi:10.1007/s00401-014-1349-0. ISSN 1432-0533. PMC 4257842. PMID 25348064.
  4. ^ Duyckaerts, Charles; Braak, Heiko; Brion, Jean-Pierre; Buée, Luc; Del Tredici, Kelly; Goedert, Michel; Halliday, Glenda; Neumann, Manuela; Spillantini, Maria Grazia; Tolnay, Markus; Uchihara, Toshiki (May 2015). "PART is part of Alzheimer disease". Acta Neuropathologica. 129 (5): 749–756. doi:10.1007/s00401-015-1390-7. ISSN 1432-0533. PMC 4405349. PMID 25628035.
  5. ^ Jellinger, Kurt A.; Alafuzoff, Irina; Attems, Johannes; Beach, Thomas G.; Cairns, Nigel J.; Crary, John F.; Dickson, Dennis W.; Hof, Patrick R.; Hyman, Bradley T.; Jack, Clifford R.; Jicha, Gregory A. (May 2015). "PART, a distinct tauopathy, different from classical sporadic Alzheimer disease". Acta Neuropathologica. 129 (5): 757–762. doi:10.1007/s00401-015-1407-2. ISSN 1432-0533. PMC 4534004. PMID 25778618.
  6. ^ a b Besser, Lilah M.; Crary, John F.; Mock, Charles; Kukull, Walter A. (2017-10-17). "Comparison of symptomatic and asymptomatic persons with primary age-related tauopathy". Neurology. 89 (16): 1707–1715. doi:10.1212/WNL.0000000000004521. ISSN 1526-632X. PMC 5644462. PMID 28916532.
  7. ^ a b c d e f Josephs, Keith A.; Murray, Melissa E.; Tosakulwong, Nirubol; Whitwell, Jennifer L.; Knopman, David S.; Machulda, Mary M.; Weigand, Stephen D.; Boeve, Bradley F.; Kantarci, Kejal (2017-02-03). "Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART)". Acta Neuropathologica. 133 (5): 705–715. doi:10.1007/s00401-017-1681-2. ISSN 1432-0533. PMC 6091858. PMID 28160067.
  8. ^ a b Santa-Maria, Ismael; Haggiagi, Aya; Liu, Xinmin; Wasserscheid, Jessica; Nelson, Peter T.; Dewar, Ken; Clark, Lorraine N.; Crary, John F. (2012-11-01). "The MAPT H1 haplotype is associated with tangle-predominant dementia". Acta Neuropathologica. 124 (5): 693–704. doi:10.1007/s00401-012-1017-1. ISSN 1432-0533. PMC 3608475. PMID 22802095.
  9. ^ a b Jefferson-George, Kyra S.; Wolk, David A.; Lee, Edward B.; McMillan, Corey T. (2017-03-16). "Cognitive decline associated with pathological burden in primary age-related tauopathy". Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 13 (9): 1048–1053. doi:10.1016/j.jalz.2017.01.028. ISSN 1552-5279. PMC 5585025. PMID 28322204.
  10. ^ a b c Saint-Aubert, Laure; Lemoine, Laetitia; Chiotis, Konstantinos; Leuzy, Antoine; Rodriguez-Vieitez, Elena; Nordberg, Agneta (20 February 2017). "Tau PET imaging: present and future directions". Molecular Neurodegeneration. 12 (1): 19. doi:10.1186/s13024-017-0162-3. ISSN 1750-1326. PMC 5319037. PMID 28219440.
  11. ^ Pierce, Aimee L.; Kawas, Claudia H. (2017-03-21). "Dementia in the oldest old: Beyond Alzheimer disease". PLOS Medicine. 14 (3): e1002263. doi:10.1371/journal.pmed.1002263. ISSN 1549-1676. PMC 5360213. PMID 28323827.
  12. ^ a b c d e Josephs, Keith A. (2017-08-01). "Current Understanding of Neurodegenerative Diseases Associated With the Protein Tau". Mayo Clinic Proceedings. 92 (8): 1291–1303. doi:10.1016/j.mayocp.2017.04.016. PMC 5613938. PMID 28778262.
  13. ^ Braak, Heiko; Del Tredici, Kelly (2014-12-01). "Are cases with tau pathology occurring in the absence of Aβ deposits part of the AD-related pathological process?". Acta Neuropathologica. 128 (6): 767–772. doi:10.1007/s00401-014-1356-1. ISSN 1432-0533. PMID 25359108. S2CID 33681944.
  14. ^ Duyckaerts, Charles; Braak, Heiko; Brion, Jean-Pierre; Buée, Luc; Del Tredici, Kelly; Goedert, Michel; Halliday, Glenda; Neumann, Manuela; Spillantini, Maria Grazia (2015-05-01). "PART is part of Alzheimer disease". Acta Neuropathologica. 129 (5): 749–756. doi:10.1007/s00401-015-1390-7. ISSN 1432-0533. PMC 4405349. PMID 25628035.
  15. ^ Jellinger, Kurt A.; Alafuzoff, Irina; Attems, Johannes; Beach, Thomas G.; Cairns, Nigel J.; Crary, John F.; Dickson, Dennis W.; Hof, Patrick R.; Hyman, Bradley T. (2015-05-01). "PART, a distinct tauopathy, different from classical sporadic Alzheimer disease". Acta Neuropathologica. 129 (5): 757–762. doi:10.1007/s00401-015-1407-2. ISSN 1432-0533. PMC 4534004. PMID 25778618.
  16. ^ Huang, Yadong; Mucke, Lennart (2012-03-16). "Alzheimer Mechanisms and Therapeutic Strategies". Cell. 148 (6): 1204–1222. doi:10.1016/j.cell.2012.02.040. ISSN 0092-8674. PMC 3319071. PMID 22424230.
  17. ^ a b Lasagna-Reeves, Cristian A.; Castillo-Carranza, Diana L.; Guerrero-Muñoz, Marcos J.; Jackson, George R.; Kayed, Rakez (2010-11-30). "Preparation and Characterization of Neurotoxic Tau Oligomers". Biochemistry. 49 (47): 10039–10041. doi:10.1021/bi1016233. ISSN 0006-2960. PMID 21047142.
  18. ^ a b c d e f g h Luo, Wenjie; Dou, Fei; Rodina, Anna; Chip, Sophorn; Kim, Joungnam; Zhao, Qi; Moulick, Kamalika; Aguirre, Julia; Wu, Nian (2007-05-29). "Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies". Proceedings of the National Academy of Sciences of the United States of America. 104 (22): 9511–9516. Bibcode:2007PNAS..104.9511L. doi:10.1073/pnas.0701055104. ISSN 0027-8424. PMC 1890525. PMID 17517623.
  19. ^ a b c d e Annadurai, Narendran; Agrawal, Khushboo; Džubák, Petr; Hajdúch, Marián; Das, Viswanath (November 2017). "Microtubule affinity-regulating kinases are potential druggable targets for Alzheimer's disease". Cellular and Molecular Life Sciences. 74 (22): 4159–4169. doi:10.1007/s00018-017-2574-1. ISSN 1420-9071. PMC 11107647. PMID 28634681. S2CID 10847883.
  20. ^ a b c Moszczynski, Alexander J.; Yang, Wencheng; Hammond, Robert; Ang, Lee Cyn; Strong, Michael J. (2017-01-11). "Threonine175, a novel pathological phosphorylation site on tau protein linked to multiple tauopathies". Acta Neuropathologica Communications. 5 (1): 6. doi:10.1186/s40478-016-0406-4. ISSN 2051-5960. PMC 5225652. PMID 28077166.
  21. ^ a b Santa-Maria, Ismael; Alaniz, Maria E.; Renwick, Neil; Cela, Carolina; Fulga, Tudor A.; Vactor, David Van; Tuschl, Thomas; Clark, Lorraine N.; Shelanski, Michael L. (2015-02-02). "Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau". The Journal of Clinical Investigation. 125 (2): 681–686. doi:10.1172/JCI78421. ISSN 0021-9738. PMC 4319412. PMID 25574843.
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