Targeting Abnormal Tau Phosphorylation for Alzheimer’s Therapeutics

Keywords

Alzheimer’s disease - phosphorylation - tau - GSK-3β - CDK5

Introduction

Alzheimer’s disease (AD) is a degenerative neurological condition that gradually diminishes memory and cognitive functions. It accounts for a significant portion of dementia cases, ranging from 50% to 75%. In the United States, roughly 6.5 million individuals aged 65 and above have been diagnosed with clinical AD in 2021 [1]. Unless medical advances are made to prevent, delay, or cure AD, this number is projected to rise to 13.8 million by 2060. The total medical expenses for AD and other dementia patients will escalate from $ 321 billion in 2022 to nearly $1 trillion by 2050. Furthermore, individuals with AD or related dementia conditions are more prone to developing other chronic ailments, resulting in escalating healthcare costs. Consequently, it has become a major global health concern [2].

The therapeutic approaches for AD are primarily focused on two signature abnormalities: extracellular plaque formation of β-amyloid (Aβ) and intraneuronal neurofibrillary tangles (NFTs) created by hyperphosphorylated tau [3]. The Aβ peptide, which ranges from a total of 39 to 43 amino acids in length, is a result of the cleavage of the amyloid precursor protein (APP). Despite being widely recognized as the primary culprit for AD genesis, the Aβ peptide also plays a vital role in numerous physiological processes such as memory consolidation, promotion of neuronal growth, safeguarding against toxins and pathogens, etc. [4]. In individuals with normal cognitive function, the concentration of Aβ40 in cerebrospinal fluid (CSF) is approximately 2–3 ng/ml, while that of Aβ42 is around 0.7–0.8 ng/ml. Elevated production or reduced clearance of Aβ peptides, or a combination of both, can lead to the accumulation of inflammatory SPs, which can impair cell signaling pathways, resulting in subsequent synaptic degeneration, neuronal loss, and cognitive function decline. Oligomeric Aβ has high neurotoxicity, with Aβ40 and Aβ42 isoforms being the primary culprits that aggregate and form Aβ plaques in the brain. However, autopsies of healthy individuals who had no history of cognitive impairment before death also showed the presence of Aβ plaques in their brains. Therefore, the existence of Aβ plaque buildup does not necessarily correlate with abnormal clinical findings [5] [6] [7] [8].

Tau, a significant protein involved in Alzheimer’s disease (AD), is a microtubule-associated protein (MAP) that is soluble in nature. In normal physiological conditions, tau plays a pivotal role in maintaining the stability of neuronal microtubules, thereby preserving neuronal morphology and physiology. Typically, tau is found in axons and is composed of a family of six isomeric forms ranging from 352 to 441 amino acids in length with sizes ranging from 37 to 46 KD, which arise from the MAPT gene’s exons 2, 3, and 10 alternative splicing as shown in [Fig. 1]. Tau is a protein that lacks a defined structure, which can stabilize microtubules, control their assembly, and influence the growth and morphology of neurons. When there are pathological conditions such as AD, PSP, FTD, or other neurodegenerative diseases, tau’s abnormal assembly gives rise to insoluble aggregates that accompany a range of neurodegenerative diseases such as synaptic dysfunction and nerve cell death [9] [10]. During the progression of AD, tau aggregates abnormally to form NFTs that exist in a characteristic distribution pattern, which allows differentiation into six stages, Braak grades, including transentorhinal stages I–II (clinically silent cases), limbic stage III–IV (incipient AD), and neocortical stages V–VI (fully developed AD). Based on the pathologic features of tau, prion-like aggregation and transmission of tau have been suggested. Pathologic tau acts as a template to induce conformational changes in normal tau protein, making it more likely to aggregate and causing more tau pathology in peripheral regions, resulting in the spread of tau pathology to wider brain regions. Research has demonstrated that AD patients have a substantial accumulation of tau protein in brain tissue compared to healthy control groups [10] [11] [12] [13] [14] [15].

Fig. 1 Illustrates a schematic representation of the protein structures of tau, which consists of six isoforms of 352–441 amino acids, namely 2N4R, 2N3R, 1N4R, 1N3R, 0N4R, and 0N3R, resulting from alternative splicing of exon 2 (E2), E3, and E10. Tau has four regions, namely N-terminus, proline-rich domain, microtubule-binding domain, and C-terminus.

The phosphorylated isomeric forms of tau help stabilize microtubules, with the 4R tau isoform promoting microtubule assembly more than the 3R isoform. However, when tau becomes hyperphosphorylated, it disturbs microtubule assembly and sequesters MAPs into paired helical filaments (PHFs), which are insoluble entities that damage cytoplasmic scaffolding and impede axonal transport, ultimately leading to neurodegeneration. Furthermore, aggregated tau protein forms neurofibrillary tangles (NFTs), which are a fundamental pathological finding in AD. Autopsy studies of AD-affected neocortical and CA1 regions reveal a direct correlation between the location of tau pathology and the severity and progression of the disease [16] [17] [18].

Nevertheless, growing evidence suggests that there is a two-way interaction between Aβ and tau. Elevated CSF tau levels were also observed in APP/PS1 transgenic mice that overexpress Aβ, whereas tau deficiency mitigated Aβ deposition. The combination of Aβ and tau synergistically impairs glucose metabolism, induces brain atrophy in AD brain, and results in the deterioration of cognitive function. Alzheimer’s disease (AD) is a neurodegenerative illness that is linked to age and classified into two subtypes based on the onset of symptoms: early-onset AD (EOAD), which occurs before the age of 65, and late-onset AD (LOAD), which usually occurs after the age of 65. LOAD is the most prevalent form of AD and is a multifactorial disease caused by genetics, aging, environmental factors, lifestyle, and chronic illnesses like obesity. EOAD accounts for only 10% of all AD cases, and a mere 5% of EOAD patients have a pathogenic variant in the AD genes (APP, PSEN1, and PSEN2) or the apolipoprotein E (APOE) ε4 allele. The pathogenesis of EOAD remains largely unknown in most patients [19] [20] [21] [22] [23] [24] [25].

Currently, the etiological theories regarding Alzheimer’s disease mainly comprise the amyloid cascade theory, tau theory, inflammatory theory, cholinergic theory, among others. Among them, the amyloid cascade theory is the most widely accepted. However, the majority of anti-Aβ drugs have not demonstrated satisfactory therapeutic efficacy over the past twenty years. It is a promising development that aducanumab, a humanized recombinant monoclonal antibody that targets Aβ, has become the first disease-modifying therapy (DMT) drug for AD in 2021, approved by an expedited pathway of the US Food and Drug Administration (FDA). Nonetheless, the approval, which was based on reduced amyloid markers and its clinical efficacy, has sparked controversy. In January 2023, another monoclonal antibody against Aβ called lecanemab was approved by the FDA for the treatment of early AD, also through its accelerated approval pathway [26] [27] [28].

Lecanemab exhibited significant reduction in brain amyloid accumulation in early-stage Alzheimer’s disease (AD) and moderate cognitive decline compared to placebo over an 18-month period, albeit with the occurrence of adverse effects [29]. Further verification is essential to establish the effectiveness and long-term safety of these drugs. Additionally, it is imperative to reassess the amyloid cascade hypothesis and explore alternative targets such as anti-tau drug development for AD, given mounting evidence that cognitive dysfunction and disease severity are more closely linked to tau pathology [30]. Inflammatory responses, particularly neuroinflammation, are implicated in the entire AD pathogenesis process and also associated with cognitive dysfunction. Hence, this review concentrates on tau pathology’s pathological changes in AD progression and recent research on the interdependent regulation and influence of neuroinflammation and tau pathology. The current clinical drug development centered on the tau and inflammation hypotheses is also analyzed. This review offers novel insights into AD pathogenesis and drug treatment strategies [31] [32].

Pathological state of tau

In 1975, the discovery of Tau marked a significant milestone. This microtubule-associated protein is highly expressed and soluble in neurons across the central nervous system (CNS). It is predominantly present in the axons of neurons and plays a pivotal role in binding to microtubules, thereby enhancing assembly and regulating stability. This function is critical in neurite outgrowth, cell shape and polarity, and intracellular cargo transport, including neurotransmitters. The MAPT gene on chromosome 17q21 encodes human tau, comprising 16 exons [33] [34] [35]. Alternative splicing of exons 2 and 3 of the tau gene in the human brain results in three isoforms with 0, 1, or 2 N-terminal repeats (0N, 1N, 2N). The absence or presence of exon 10 produces tau species with either three (3R) or four (4R) carboxyl-terminal microtubule-binding domain. Thus, within the human brain, six tau isoforms of varying lengths ranging from 352 to 441 amino acids are expressed, with their expression being developmentally regulated. In the adult brain, all six isoforms are present with roughly equivalent 4R and 3R isoforms, while the fetal brain expresses solely 0N3R tau. The 4R tau isoforms demonstrate greater affinity when binding to microtubules compared to the 3R isoforms. Furthermore, research has demonstrated that certain mutations within the tau gene affect the alternative splicing of exon 10, leading to an altered 4R:3R ratio, a critical element of primary tauopathies. These disorders belong to a subgroup of FTLD illnesses characterized by neuronal and glial tau inclusions, with predominant atrophy in the frontal and temporal lobes [36] [37] [38].

Pathological tau in AD undergoes severe post-translational modifications (PTMs), which initiate prior to the formation of neurofibrillary tangles (NFTs), even decades before the manifestation of symptoms. It is crucial to note that not all PTMs lead to pathological consequences, as the location, type, and extent of modification play a decisive role. Hyperphosphorylation, the most extensively studied PTM of tau, was one of the earliest modifications identified. Previous investigations have demonstrated that aggregated tau, isolated from AD brains, has an overall phosphorylation level that is 3–4 times higher than healthy controls (2–3 mol per protein) [39]. Hyperphosphorylated tau leads to reduced binding ability with microtubules, as well as decreased stability of microtubules. The dissociation of tau leads to self-aggregation, resulting in the formation of oligomers and NFTs. This process disrupts the normal structure of cells and inhibits intracellular material exchange, leading to aggregation and ultimately, neurodegeneration. Furthermore, acetylation and N-glycosylation have been found to increase in AD, with acetylation inhibiting tau protein degradation and promoting pathological tau aggregation and propagation [40] [41] [42] [43] [44] [45]. N-Glycosylation, on the other hand, stimulates tau polymerization by promoting phosphorylation and conformational changes. Additionally, nitration of the Tyr29 site of tau, found only in AD patients, significantly affects tau polymerization and facilitates tau aggregation as shown in [Fig. 2].

Fig. 2 Illustrates the therapeutic mechanism of targeting tau protein.

The cleavage modification of caspase in AD patient brain also plays a key role. Caspases 2 and 3 cleave the C-terminus at Asp314 and Asp421, respectively, while caspase 6 cleaves the N-terminus. In addition to affecting microtubule binding and aggregation, cleaving the C-terminal of tau has been linked to mitochondrial and synaptic damage [46] [47] [48] [49] [50]. However, it is important to note that not all post-translational modifications (PTMs) contribute to the acceleration of tau pathology and Alzheimer’s disease (AD) progression. In fact, ubiquitination has been found to aid in the degradation of tau through autophagy and proteasome, while also inhibiting tau aggregation and maintaining microtubule stability. Additionally, lysine methylation is a normal PTM observed in tau in the human brain and can help to protect against pathological tau aggregation to some extent as shown in [Table 1]. Another tau PTM, dityrosine (DiY) cross-links, is induced by oxidative stress and has been observed on human AD-derived tau oligomers and PHFs. Interestingly, DiY cross-links can facilitate the formation of non-toxic, soluble tau oligomers, inhibit the formation of β-sheets and further extension of prefibrils, and increase the insolubility and stability of tau fibrils in AD [51] [52] [53] [54].

Table 1 The investigation of the modalities and advancements of drugs that are aimed at tau protein therapy is being conducted [55].

Entry	Drug	Targeting Site	Action
1	LMTM	Alzheimer’s Disease (phase 3)	Aggregation inhibitors
2	Lithium	MCI (phase 4), expected to be completed by 2023	GSK-3β inhibitor
3	LY3372689	Alzheimer’s Disease (phase 2)	O-GlcNAcase inhibitor
4	Tideglusib	Alzheimer’s Disease (discontinued)	GSK-3β inhibitor
5	Curcumin	Alzheimer’s Disease (phase 2)	Aggregation inhibitors
6	Epothilone	Alzheimer’s Disease (discontinued)	Microtubule stabilizers
7	Gosuranemab	Alzheimer’s Disease (discontinued)	A humanized IgG4 monoclonal antibody targeting the N-terminal region of tau protein
8	Bepranemab	Alzheimer’s Disease (phase2), will run until November 2025.	A humanized IgG4 monoclonal antibody targeting tau 235–250 near the MTBR of tau
9	Tilavonema	Alzheimer’s Disease (discontinued)	A humanized IgG4 antibody recognizes 25–30 aa of tau and targets extracellular tau
10	Sodium selenate	Alzheimer’s Disease (phase 2)	PP2A activators

Phosphorylation state inhibitor

The tau protein comprises multiple phosphorylation sites that are integral to its ability to bind to microtubules. The degree of phosphorylation determines the protein’s affinity for microtubules, with hyperphosphorylated tau exhibiting decreased affinity and even a loss of the ability to bind altogether [55] [56]. This results in a compromised cytoskeleton, which could lead to neuronal death if hyperphosphorylated tau accumulates in neurons to form PHFs. Maintaining normal neuronal physiological functions necessitates inhibiting tau hyperphosphorylation. The phosphorylation level of tau is governed by a balance of protein kinases and phosphatases, and any disruption to this balance is linked to abnormal tau phosphorylation observed in AD, particularly the hyperactivation of glycogen synthase kinase 3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5) and the inhibition of protein phosphatase-2A (PP2A). Hampering tau pathology and AD therapy may be achieved by inhibiting protein kinase activity and increasing phosphatase activity [57].

GSK-3β inhibitors

Tideglusib (also known as NP031112, Nypta, Zentylor, NP12) is a GSK-3β irreversible inhibitor that is widely examined as a tau kinase inhibitor. Its inhibition effectively counteracts tau hyperphosphorylation. Mouse entorhinal cortex and hippocampus preclinical studies have indicated that tideglusib can reduce a range of disease outcomes including tau phosphorylation, Aβ deposition, neuron loss, and gliosis, and reverse spatial memory impairment in transgenic mice. Furthermore, tideglusib’s neuroprotective, anti-inflammatory, and neurogenesis-inducing effects have also been validated in animal models [58]. In a phase 2 clinical trial with mild to moderate AD patients, tideglusib demonstrated an acceptable safety profile for a short-term (26 weeks) treatment, with the exception of a transient increase in serum transaminase levels and diarrhea (14–18% in active, 11% placebo). However, it was not successful in slowing cognitive dysfunction, and only a small number of patients showed significant reductions of β-secretase in CSF. At present, the study of tideglusib in AD has been terminated. Lithium has been widely used as a medication for bipolar disorder and has been examined for its ability to inhibit GSK-3β in the treatment of AD [59].

While clinical trials have not shown significant improvements in cognitive scores or CSF-based biomarker concentrations after 10 weeks of lithium treatment for mild or mild-to-moderate AD, a 12-month double-blind trial for patients with amnestic mild cognitive impairment (MCI) has demonstrated promising results. The group treated with lithium showed decreased levels of phosphorylated tau in CSF and improved cognitive ability compared to the control group receiving a placebo. Furthermore, the use of lithium was deemed safe and well-tolerated at a serum concentration range of 0.25–0.5 mmol/l. In patients diagnosed with AD, the effectiveness of microdose lithium (300 μg/day) in preventing cognitive loss was demonstrated during a 15-month study. Previous studies had failed to discover a significant impact of lithium on cognition or AD-related biomarkers, potentially due to the high incidence of side effects such as renal and neurologic dysfunction, endocrine abnormalities, and high withdrawal rates. Furthermore, shorter follow-up periods and the inclusion of patients with cognitive degradation related to the later stage may have contributed to these findings. Overall, clinical evidence suggests that long-term microdose lithium therapy is necessary for a positive outcome, and the use of microdose lithium could potentially solve the toxicity issues that have hindered medication development. Currently, there is a phase 4 clinical trial investigating the use of lithium in patients with MCI, which is set to conclude in 2023 [60].

CDK5 inhibitors

CDK5 is a protein kinase that is activated through interaction with its activators, namely p35 and p39, as well as their cleavage products, p25 and p29, respectively. This activation governs several cellular processes in neurons. The dysregulation of CDK5 is primarily attributed to the formation and accumulation of neurotoxic p25 and p29. The resultant hyperactivation and mislocalization of CDK5 lead to the hyperphosphorylation of its substrates. CDK5 phosphorylates Tau, which is a crucial substrate of CDK5, and causes it to disassociate from microtubules, self-aggregate, and eventually form PHFs and insoluble NFTs in neurons[61] [62] [63] [64] [65].

Studies have demonstrated that knocking down CDK5 in triple transgenic (3xTg) AD mice, as well as inhibiting CDK5 with CDK5 inhibitory peptide in vitro, can reduce tau hyperphosphorylation and NFT formation. Minocycline has been found to alleviate Alzheimer’s disease (AD)-like symptoms and improve cognitive impairment by inhibiting the CDK5/p25 signaling pathway. During the advanced stages of the disease, CDK5 primes phosphorylation sites on tau for GSK-3β, which then synergistically promotes the GSK-3β-mediated tau hyperphosphorylation. However, a previous study has reported that the administration of CP681301, a CDK5 inhibitor, actually enhanced tau phosphorylation in p25-overexpressing transgenic mice, contradicting the conventional understanding of the synergistic relationship between CDK5 and GSK-3β. CDK5 can indirectly phosphorylate GSK-3β at S9 and inhibit its activity, suggesting that CDK5 inhibition may enhance tau phosphorylation through the activation of GSK3β. Despite contradictory reports regarding the effect of CDK5 on tau phosphorylation, an equally significant concern is the lack of tau-specificity exhibited by CDK5 inhibitors. Given that CDK5 can phosphorylate molecules other than tau, greater attention should be devoted to the development of tau-targeting agents with CDK5 inhibitory activity. As of yet, no successful small molecule candidates have been identified as selective inhibitors of CDK5 kinase activity [66] [67] [68].

Phosphatase activator

The major constituents of phosphatases in the human brain are PP2A, PP5, PP1, and PP2B, comprising 71%, 11%, 10%, and 7% of the total tau dephosphorylation activity, respectively. In individuals with Alzheimer’s disease (AD), there is a noticeable decrease in the total phosphatase activity, PP2A activity, and PP5 activity towards tau, however, an increase in PP2B activity is also observed. The downregulation of PP2A activity may lead to abnormal hyperphosphorylation of tau, which can result in a 50% reduction in its activity in AD brain, consistent with the level of tau phosphorylation. Conversely, PP1 and PP5 activity is much less downregulated. In vitro, co-incubation of tau aggregates with PP2A has been found to restore the binding of tau to microtubules to a level similar to the control group (approximately 80%). Therefore, PP2A is the primary tau phosphatase, and its activators have promising potential for AD treatment [69] [70].

Conclusion

In conclusion, Alzheimer’s disease (AD) is a devastating neurodegenerative condition characterized by the gradual loss of memory and cognitive functions. It represents a significant global health concern, with a rising number of individuals affected and escalating healthcare costs associated with its management. Current therapeutic approaches primarily target two hallmark abnormalities in AD: the extracellular plaque formation of β-amyloid (Aβ) and the intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. While the amyloid cascade theory has been the dominant hypothesis in AD research, recent developments, such as the approval of aducanumab and lecanemab as disease-modifying therapies, have sparked controversy and raised questions about the role of tau pathology. Growing evidence suggests that the interaction between Aβ and tau is complex, with both proteins contributing to disease progression. Pathological tau, particularly its hyperphosphorylation, plays a critical role in disrupting microtubule stability, cytoskeletal function, and neuronal health. Various post-translational modifications of tau have been identified in AD, contributing to its aggregation and the formation of NFTs. Targeting tau pathology through drugs that modulate tau phosphorylation, such as GSK-3β inhibitors and CDK5 inhibitors, has shown promise in preclinical studies and some clinical trials. Furthermore, the balance between protein kinases and phosphatases, especially protein phosphatase-2A (PP2A), is crucial for regulating tau phosphorylation. Activating tau-specific phosphatases like PP2A is an emerging therapeutic approach with potential benefits for AD treatment. The landscape of AD drug development is evolving, with a growing focus on tau-targeted therapies and reevaluating the amyloid cascade hypothesis. Future research will likely continue to explore the intricate relationship between Aβ and tau and seek to develop more effective treatments for this devastating disease. In addition to tau-focused therapies, understanding the role of neuroinflammation in AD and its interplay with tau pathology is an important area of investigation. Advances in our knowledge of these aspects of AD pathogenesis may lead to innovative treatment strategies.

In summary, AD remains a challenging and multifaceted disease, and while significant progress has been made in understanding its molecular underpinnings, there is still much work to be done in developing effective therapies and ultimately finding a cure for this devastating condition.

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