Advances in Tau Protein Research and Therapeutic Strategies for Alzheimer’s Disease


Tau proteins, integral to neuronal function, are critical for the stabilization of microtubules (MTs) primarily within axons. These proteins, under normal physiological conditions, maintain MT structure and facilitate essential intracellular transport mechanisms (Brunden et al., 2009; Lee et al., 2011). However, when tau proteins undergo phosphorylation, they dissociate from MTs, leading to significant neurodegenerative consequences (Ballatore et al., 2007).

In Alzheimer’s disease (AD) and other tauopathies, soluble tau monomers accumulate abnormally in synaptic compartments, transitioning from a monomeric state to oligomeric forms, and eventually forming neurofibrillary tangles (NFTs) (Fein et al., 2008; Tai et al., 2012). NFTs are a hallmark of tauopathies, including AD, with their density and the levels of soluble tau closely correlated with the progression of the disease and cognitive decline (Greenberg and Davies, 1990; Yoshida and Ihara, 1993; Gotz et al., 2008; Koss et al., 2016).

Synaptic Dysfunction and Tau Pathology

Research has shown that synaptic dysfunction precedes the emergence of NFTs in tauopathy model mice, indicating that early intervention could be crucial in altering disease progression (Yoshiyama et al., 2007). Specifically, in rodent brainstem slices, synaptic dysfunction induced by soluble tau accumulation has been modeled at the calyx of Held. Here, the direct infusion of human recombinant 4R-tau into presynaptic terminals leads to an activity-dependent rundown of excitatory postsynaptic currents (EPSCs) (Hori et al., 2022). This phenomenon is primarily attributed to impaired vesicle endocytosis caused by tau-induced MT over-assembly, which sequesters cytosolic dynamin, thereby disrupting dynamin-dependent vesicular fission during endocytosis (Shpetner and Vallee, 1992; Hinshaw and Schmid, 1995; Takei et al., 1995).

Rescue of Synaptic Function via MT Disassembly

The detrimental effects of tau on synaptic function can be mitigated by disassembling MTs or by specifically inhibiting the interaction between dynamin and MTs. The synthetic dodecapeptide PHDP5, derived from the dynamin 1 pleckstrin-homology (PH) domain, has been shown to block the dynamin-MT interaction effectively. When loaded into presynaptic terminals in brain slices, PHDP5 rescues tau-induced impairments of vesicle endocytosis and synaptic transmission (Hori et al., 2022).

In Vivo Therapeutic Potential of PHDP5

Building on these findings, researchers explored the in vivo potential of PHDP5 in rescuing learning and memory deficits in tauopathy and AD transgenic mouse models. Using Tau609 tauopathy model mice, which overexpress the human 4R-tau splice variant, and the 3xTg-AD model mice, which express mutated forms of presenilin1, amyloid precursor protein, and tau, PHDP5 was administered intranasally (Umeda et al., 2013; Oddo et al., 2003). This administration route was chosen to bypass the blood-brain barrier and to ensure efficient delivery to the hippocampus (Agrawal et al., 2018).

In these studies, the effect of PHDP5 on spatial learning and memory was assessed using the Morris water maze (MWM). Results demonstrated that PHDP5-treated Tau609 and 3xTg-AD mice exhibited significant improvements in learning and memory, performing comparably to wild-type (WT) mice. In contrast, mice treated with a scrambled peptide (SPHDP5) showed negligible improvements (Hori et al., 2022).

Implications for Alzheimer’s Disease Treatment

These findings suggest that PHDP5 could be a promising therapeutic candidate for AD, potentially alleviating memory impairments and improving cognitive functions. Furthermore, the beneficial effects of PHDP5 in synaptic transmission underscore the importance of targeting synaptic dysfunction in the early stages of AD to prevent neuronal damage and cognitive decline.

Broader Applications and Future Directions

The mechanisms underlying tau-induced synaptic dysfunction are not unique to AD but also relevant to other neurodegenerative diseases such as Parkinson’s disease (PD). For instance, intra-terminal loading of α-synuclein, another protein implicated in PD, impairs vesicle endocytosis and synaptic transmission, similar to tau (Eguchi et al., 2017). Therefore, the dynamin-MT interaction appears to be a common pathway that could be targeted for therapeutic interventions across multiple neurodegenerative diseases.

Potential Side Effects and Considerations

While PHDP5 shows promise, potential side effects must be considered. The dynamin-MT interaction is essential for various physiological processes, including the structure and function of kidney podocytes (Soda et al., 2012; La et al., 2020). Thus, systemic inhibition of this interaction could impair renal function. However, the intranasal administration route of PHDP5 minimizes systemic exposure, reducing the risk of such side effects. Moreover, potential impacts on the neuronal system, such as Charcot-Marie-Tooth disease-like symptoms, need careful evaluation (Zuchner et al., 2005; Tanabe and Takei, 2009).

Delivery Mechanisms and Cellular Uptake

The transactivator of transcription (TAT) cell-penetrating peptide (CPP) facilitates the efficient cellular uptake of therapeutic peptides. The cationic nature of TAT, due to its poly-arginine and other positively charged residues, allows it to bind to negatively charged glycoproteins on cell membranes, promoting internalization without the need for receptor involvement (Borrelli et al., 2018; Arafiles et al., 2023). This property of TAT was utilized to conjugate it to PHDP5, enhancing its delivery to the hippocampus and subsequently improving cognitive functions in AD model mice.

In conclusion, the development of PHDP5 represents a significant advancement in the understanding and potential treatment of Alzheimer’s disease. By targeting the molecular and cellular mechanisms of tau-induced synaptic dysfunction, PHDP5 offers a promising therapeutic strategy to alleviate memory deficits and cognitive decline in AD and potentially other neurodegenerative diseases. Future research should focus on optimizing delivery methods, minimizing side effects, and exploring the broader applicability of this therapeutic approach in various tauopathies and synucleinopathies.

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