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Role of Tau Protein in Synaptic Deterioration of Alzheimer's Disease (AD)

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 24179

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Special Issue Editors

Dr. Giuseppina Amadoro

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Guest Editor

1. European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy
2. Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Fosso del Cavaliere 100, 00133 Rome, Italy
Interests: tau protein; Alzheimer's disease (AD); amyloid beta; Amyloid Precursor Protein (APP); synapse; non-AD tauopathies; immunotherapy; neurodegeneration
Special Issues, Collections and Topics in MDPI journals

Dr. Valentina Latina

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European Brain Research Institute (EBRI) Rita Levi-Montalcini, Rome, Italy
Interests: tau protein; tau cleavage; amyloid beta; Alzheimer's Disease, neurodegeneration; retina; eye degeneration; synaptotoxicity; immunotherapy; Nerve Growth Factor (NGF)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Accumulating evidence suggests that degeneration of synaptic connections is the strongest pathological correlate of cognitive decline in Alzheimer's disease (AD), an age-related neurodegenerative disorder characterized by amyloid beta (Aβ) and tau protein deposition inhibiting the synaptic plasticity of neurons. Experimental studies also indicate that tau pathology—much more strongly than Ab pathology–is the actual driver of synaptic loss and neurodegeneration in AD progression. Accumulation of soluble oligomeric species of tau leads to synaptic degeneration and memory or learning impairment in animal models, regardless of aggregation in neurofibrillary tangles (NFTs). Tau can either directly or indirectly impact synapses and alter neurotransmission by acting both on the pre- and post-synaptic sides, or on either side alone. Targeting of pathological tau restores deficits in synaptic plasticity and attenuates synaptic loss in transgenic mice, opening novel opportunities for an efficacy cure for AD in the face of disappointing Aβ-directed clinical trials. The spread of tau pathology occurs via synaptic connections, indicating that reductions in tau levels will also halt the propagation of the disease throughout the brain. Understanding the physiopathological role of tau in the synapses is crucial for the future development of therapeutic strategies aimed at preventing or reducing the progressive deterioration in cognition and brain function associated with AD pathogenesis. This Special Issue will be focused on recent advances in addressing the emerging role of tau dysmetabolism in synaptic failure in AD and its translational implications.

Dr. Giuseppina Amadoro
Dr. Valentina Latina
Guest Editors

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Keywords

Tau protein
Alzheimer’s disease
Synaptotoxicity
Neurodegeneration
Therapeutic intervention

Published Papers (4 papers)

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Research

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35 pages, 4403 KiB

Open AccessArticle

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

by Valentina Latina, Giacomo Giacovazzo, Pietro Calissano, Anna Atlante, Federico La Regina, Francesca Malerba, Marco Dell’Aquila, Egidio Stigliano, Bijorn Omar Balzamino, Alessandra Micera, Roberto Coccurello and Giuseppina Amadoro

Int. J. Mol. Sci. 2021, 22(22), 12158; https://doi.org/10.3390/ijms222212158 - 10 Nov 2021

Cited by 16 | Viewed by 4309

Abstract

Tau cleavage plays a crucial role in the onset and progression of Alzheimer’s Disease (AD), a widespread neurodegenerative disease whose incidence is expected to increase in the next years. While genetic and familial forms of AD (fAD) occurring early in life represent less than 1%, the sporadic and late-onset ones (sAD) are the most common, with ageing being an important risk factor. Intracerebroventricular (ICV) infusion of streptozotocin (STZ)—a compound used in the systemic induction of diabetes due to its ability to damage the pancreatic β cells and to induce insulin resistance—mimics in rodents several behavioral, molecular and histopathological hallmarks of sAD, including memory/learning disturbance, amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress and brain glucose hypometabolism. We have demonstrated that pathological truncation of tau at its N-terminal domain occurs into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice, and that it’s in vivo neutralization via intravenous (i.v.) administration of the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) is strongly neuroprotective. Here, we report the therapeutic efficacy of 12A12mAb in STZ-infused mice after 14 days (short-term immunization, STIR) and 21 days (long-term immunization regimen, LTIR) of i.v. delivery. A virtually complete recovery was detected after three weeks of 12A12mAb immunization in both novel object recognition test (NORT) and object place recognition task (OPRT). Consistently, three weeks of this immunization regimen relieved in hippocampi from ICV-STZ mice the AD-like up-regulation of amyloid precursor protein (APP), the tau hyperphosphorylation and neuroinflammation, likely due to modulation of the PI3K/AKT/GSK3-β axis and the AMP-activated protein kinase (AMPK) activities. Cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations occurring in STZ-infused mice were also strongly attenuated by 12A12mAb delivery. These results further strengthen the causal role of N-terminal tau cleavage in AD pathogenesis and indicate that its specific neutralization by non-invasive administration of 12A12mAb can be a therapeutic option for both fAD and sAD patients, as well as for those showing type 2 diabetes as a comorbidity. Full article

(This article belongs to the Special Issue Role of Tau Protein in Synaptic Deterioration of Alzheimer's Disease (AD))

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17 pages, 17662 KiB

Open AccessArticle

Behavioural Functions and Cerebral Blood Flow in a P301S Tauopathy Mouse Model: A Time-Course Study

by Faraz Ahmad, Hannah Mein, Yu Jing, Hu Zhang and Ping Liu

Int. J. Mol. Sci. 2021, 22(18), 9727; https://doi.org/10.3390/ijms22189727 - 8 Sep 2021

Cited by 8 | Viewed by 2814

Abstract

Tauopathies refer to a group of neurodegenerative diseases with intracellular accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) in neurons and glial cells. PS19 mice bearing the MAPT P301S mutation have been used to mimic human frontotemporal lobar degeneration. The present study was designed to systematically investigate how behavioural functions, resting cerebral blood flow (CBF) and tau pathology change in PS19 mice at 2, 4, 6, 8 and 12 months of age in a single study under one experimental condition, allowing for the cumulative assessment of age- and genotype-dependent changes. PS19 mice displayed hyperactivity and reduced anxiety levels with age, early and persistent spatial working memory deficits and reduced resting neocortical CBF. Immunoblotting and immunohistochemistry revealed age-related increases in phosphorylated tau in the brain of PS19 mice. In conclusion, the present study, for the first time, cumulatively demonstrated the time-course of changes in behavioural functions, resting CBF and tau pathology in a P301S tauopathy mouse model through their developmental span. This information provides further evidence for the utility of this model to study neurodegenerative events associated with tauopathy and tau dysfunction. Full article

(This article belongs to the Special Issue Role of Tau Protein in Synaptic Deterioration of Alzheimer's Disease (AD))

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Review

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15 pages, 660 KiB

Open AccessReview

Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction

by Giacomo Siano, Chiara Falcicchia, Nicola Origlia, Antonino Cattaneo and Cristina Di Primio

Int. J. Mol. Sci. 2021, 22(18), 10145; https://doi.org/10.3390/ijms221810145 - 20 Sep 2021

Cited by 8 | Viewed by 3708

Abstract

Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction. Full article

(This article belongs to the Special Issue Role of Tau Protein in Synaptic Deterioration of Alzheimer's Disease (AD))

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49 pages, 2837 KiB

Open AccessReview

Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies

by Jakub Sinsky, Karoline Pichlerova and Jozef Hanes

Int. J. Mol. Sci. 2021, 22(17), 9207; https://doi.org/10.3390/ijms22179207 - 26 Aug 2021

Cited by 53 | Viewed by 11976

Abstract

Tau protein plays a critical role in the assembly, stabilization, and modulation of microtubules, which are important for the normal function of neurons and the brain. In diseased conditions, several pathological modifications of tau protein manifest. These changes lead to tau protein aggregation and the formation of paired helical filaments (PHF) and neurofibrillary tangles (NFT), which are common hallmarks of Alzheimer’s disease and other tauopathies. The accumulation of PHFs and NFTs results in impairment of physiological functions, apoptosis, and neuronal loss, which is reflected as cognitive impairment, and in the late stages of the disease, leads to death. The causes of this pathological transformation of tau protein haven’t been fully understood yet. In both physiological and pathological conditions, tau interacts with several proteins which maintain their proper function or can participate in their pathological modifications. Interaction partners of tau protein and associated molecular pathways can either initiate and drive the tau pathology or can act neuroprotective, by reducing pathological tau proteins or inflammation. In this review, we focus on the tau as a multifunctional protein and its known interacting partners active in regulations of different processes and the roles of these proteins in Alzheimer’s disease and tauopathies. Full article

(This article belongs to the Special Issue Role of Tau Protein in Synaptic Deterioration of Alzheimer's Disease (AD))

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