Lysine 63-linked ubiquitination of tau oligomers contributes to the pathogenesis of Alzheimer’s disease

Puangmalai, Nicha; Sengupta, Urmi; Bhatt, Nemil; Gaikwad, Sagar; Montalbano, Mauro; Bhuyan, Arijit; Garcia, Stéphanie; McAllen, Salome; Sonawane, Minal; Jerez, Cynthia; Zhao, Yingxin; Kayed, Rakez

doi:10.1016/j.jbc.2022.101766

Cited by 40 publications

(21 citation statements)

References 92 publications

(151 reference statements)

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“…These NFTs disturb the cytoskeletal network and axonal transport. Eventually, the ubiquitination of hyperphosphorylated tau [ 216 , 217 , 218 ], associated with the dysfunction of the ubiquitin–proteasome system [ 219 ], leads to the development of oxidative stress. These abnormalities ultimately lead to synaptic and mitochondrial dysfunction and progressive neurodegeneration in AD [ 40 ].…”

Section: Molecular Mechanisms Linking T2d To Admentioning

confidence: 99%

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

Hamzé

Delangre

Tolu

et al. 2022

IJMS

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The global prevalence of diabetes mellitus and Alzheimer’s disease is increasing alarmingly with the aging of the population. Numerous epidemiological data suggest that there is a strong association between type 2 diabetes and an increased risk of dementia. These diseases are both degenerative and progressive and share common risk factors. The amyloid cascade plays a key role in the pathophysiology of Alzheimer’s disease. The accumulation of amyloid beta peptides gradually leads to the hyperphosphorylation of tau proteins, which then form neurofibrillary tangles, resulting in neurodegeneration and cerebral atrophy. In Alzheimer’s disease, apart from these processes, the alteration of glucose metabolism and insulin signaling in the brain seems to induce early neuronal loss and the impairment of synaptic plasticity, years before the clinical manifestation of the disease. The large amount of evidence on the existence of insulin resistance in the brain during Alzheimer’s disease has led to the description of this disease as “type 3 diabetes”. Available animal models have been valuable in the understanding of the relationships between type 2 diabetes and Alzheimer’s disease, but to date, the mechanistical links are poorly understood. In this non-exhaustive review, we describe the main molecular mechanisms that may link these two diseases, with an emphasis on impaired insulin and IGF-1 signaling. We also focus on GSK3β and DYRK1A, markers of Alzheimer’s disease, which are also closely associated with pancreatic β-cell dysfunction and type 2 diabetes, and thus may represent common therapeutic targets for both diseases.

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Section: Molecular Mechanisms Linking T2d To Admentioning

confidence: 99%

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

Hamzé

Delangre

Tolu

et al. 2022

IJMS

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“…This was followed by incubation with HRP-conjugated IgG anti-mouse or anti-rabbit (1:6000, GE Healthcare) secondary antibody to detect primary antibodies. ECL plus (GE Healthcare) was used for signal detection [ 44 ].…”

Section: Methodsmentioning

confidence: 99%

“…ECL plus (GE Healthcare) was used for signal detection. Finally, the selected clones (SynTCs) were tested using human and mouse brains [ 44 – 47 ].…”

Section: Methodsmentioning

confidence: 99%

Polymorphic Alpha-Synuclein Oligomers: Characterization and Differential Detection with Novel Corresponding Antibodies

et al. 2023

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The pathological hallmark of many neurodegenerative diseases is the accumulation of characteristic proteinaceous aggregates. Parkinson’s disease and dementia with Lewy bodies can be characterized as synucleinopathies due to the abnormal accumulation of the protein alpha-synuclein (α-Syn). Studies have shown amyloidogenic proteins such as α-Syn and tau can exist as polymorphic aggregates, a theory widely studied mostly in their fibrillar morphology. It is now well understood that an intermediate state of aggregates, oligomers, are the most toxic species. We have shown α-Syn, when modified by different physiological inducers, result in distinct oligomeric conformations of α-Syn. Polymorphic α-Syn oligomers exhibit distinct properties such as aggregate size, conformation, and differentially interact with tau. In this study, we confirm α-Syn oligomeric polymorphs furthermore using in-house novel α-Syn toxic conformation monoclonal antibodies (SynTCs). It is unclear the biological relevance of α-Syn oligomeric polymorphisms. Utilizing a combination of biochemical, biophysical, and cell-based assays, we characterize α-Syn oligomeric polymorphs. We found α-Syn oligomeric polymorphs exhibit distinct immunoreactivity and SynTCs exhibit differential selectivity and binding affinity for α-Syn species. Isothermal titration calorimetry experiments suggest distinct α-Syn:SynTC binding enthalpies in a species-specific manner. Additionally, we found SynTCs differentially reduce α-Syn oligomeric polymorph-mediated neurotoxicity and propagation in primary cortical neurons in a polymorph-specific manner. These studies demonstrate the biological significance of polymorphic α-Syn oligomers along with the importance of polymorph-specific antibodies that target toxic α-Syn aggregates. Monoclonal antibodies that can target the conformational heterogeneity of α-Syn oligomeric species and reduce their mediated toxicity have promising immunotherapeutic potential.

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“…Our protocol was approved by the Institutional Animal care and Use Committee of the University of Texas Medical Branch (UTMB). Primary cortical neuronal cultures were prepared and maintained as described previously ( 62 , 88 , 89 , 90 ). Briefly, cortices were isolated from C57BL/6 mice (Jackson Laboratory; 000664) during embryonic day 13 to 16.…”

Section: Methodsmentioning

confidence: 99%

Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein

Dhakal¹,

Robang²,

Bhatt³

et al. 2022

Journal of Biological Chemistry

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Lysine 63-linked ubiquitination of tau oligomers contributes to the pathogenesis of Alzheimer’s disease

Cited by 40 publications

References 92 publications

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

Polymorphic Alpha-Synuclein Oligomers: Characterization and Differential Detection with Novel Corresponding Antibodies

Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein

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