Tau-Targeted Multifunctional Nanocomposite for Combinational Therapy of Alzheimer’s Disease

A multifunctional nanocomposite based on mesoporous silica allows targeting several key links of the pathological cascade at once.

“This approach allows targeting several key links of the pathological cascade at once: from primary protein aggregates to secondary processes of inflammation and oxidative stress originating from mitochondrial dysfunction.”

Alternative targeting strategies include peptide ligands targeting hyperphosphorylated tau, BBB penetration property, small molecules binding beta-sheet structure, and electrostatic interactions.

“Alternative strategies include the use of peptide ligands targeting hyperphosphorylated tau protein [64] or the property of penetrating the BBB [58,72], as well as small molecules that bind to the beta-sheet structure of amyloid fibrils [83]. In some works, specificity is achieved through electrostatic interactions between the charged surface of Nps and negatively charged amyloid aggregates [68].”

Tau protein serves as a target far less frequently, where systems combine hyperphosphorylated tau targeting with therapies reducing oxidative stress and inhibiting Aβ aggregation.

“Tau protein serves as a target far less frequently, where systems combine hyperphosphorylated tau targeting with therapies reducing oxidative stress and inhibiting Aβ aggregation [64,72].”

A number of studies employ multimodal approaches, combining MRI with PET, SPECT, or fluorescence imaging, which compensates for the limitations of each method individually.

“A number of studies employ multimodal approaches, combining MRI with PET [64], SPECT [70,71], or fluorescence imaging [72,75], which compensates for the limitations of each method individually.”

Chen et al. developed a CeNC/IONC/MSN-T807 nanocomposite integrating IONCs for MRI/PET bimodal imaging, CeNCs as an antioxidant, and methylene blue as a tau aggregation inhibitor loaded into mesoporous silica Nps.

“Chen et al. [64] developed a CeNC/IONC/MSN-T807 nanocomposite integrating superparamagnetic iron oxide nanocrystals (IONCs) for MRI/PET bimodal imaging, nanoceria (CeNCs) as an antioxidant, and methylene blue as a tau aggregation inhibitor, loaded into mesoporous silica Nps.”

Much less frequently, the target of therapy is tau protein, although Chen et al. and Gu et al. demonstrated a reduction in its hyperphosphorylation due to antioxidant action or activation of neuroprotective signaling cascades.

“Much less frequently, the target of therapy is tau protein, although the works of Chen et al. [64] and Gu et al. [72] demonstrated a reduction in its hyperphosphorylation due to antioxidant action or activation of neuroprotective signaling cascades.”

The effectiveness of therapy is confirmed in most studies on cellular models, where a significant increase in survival of neuronal cells upon exposure to toxic concentrations of Aβ is shown.

“The effectiveness of therapy is confirmed in most studies on cellular models, where a significant increase in the survival of neuronal cells upon exposure to toxic concentrations of Aβ is shown [29,64,72,76,77,78,80,83].”

Many studies include an antioxidant component aimed at reducing ROS and an anti-inflammatory effect via delivery of immunosuppressants.

“Many studies also include an antioxidant component aimed at reducing the level of ROS [64,72,78,80,83], and an anti-inflammatory effect, implemented through the delivery of immunosuppressants [70,71].”

Leading examples exhibit true component synergy.

“Leading examples exhibit true component synergy [64,69,83].”

In animal models, reduction in amyloid plaque burden, decrease in neuroinflammation and oxidative stress, and improvement in cognitive functions in behavioral tests have been demonstrated.

“In animal models, a reduction in the burden of amyloid plaques [58,68,75], a decrease in neuroinflammation and oxidative stress, as well as an improvement in cognitive functions in behavioral tests [58,64,72,73,83,85] have been demonstrated.”