Alzheimer's disease (AD) is a neurological condition marked by a subtle onset and progressive decline in mental and behavioral skills. Current intervention for AD is mainly symptomatic treatments such as acetylcholine esterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) antagonists. Recently, two drugs (aducanumab and lecanemab-irmb) aimed at the reduction of amyloid beta plaques were approved by the Food and Drug Administration in the United States under an accelerated approval pathway for which verification of clinical benefits in confirmatory trials are required [1], [2]. Hence a safe and more effective therapeutic agent is needed since the mechanisms of AD are still in a mist, and the drugs in current clinical use are limited. The amyloid cascade and the protein tau hyperphosphorylation are two common hypotheses depicting the pathological causes of AD.

According to the amyloid cascade hypothesis, the abnormally accumulated amyloid beta (Aβ) plaques in the brain mainly consisted of Aβ peptides [3]. These peptides containing 39–44 amino acids were produced through the consecutive cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase [4]. Aβ40 is the more abundant form, accounting for about 90% of Aβ production in the brain, while Aβ42 makes up about 10%. Studies have shown that Aβ42 was more likely to aggregate into toxic oligomers and fibrils than Aβ40 [5], [6]. Furthermore, Aβ42 has been shown to be more strongly associated with cognitive decline and AD pathology than Aβ40 [7]. In addition, mutations in the APP gene that increased the production of Aβ42 were associated with familial forms of AD [8]. Overall, while both Aβ40 and Aβ42 were involved in the pathogenesis of AD, Aβ42 was considered to be more toxic and pathogenic than Aβ40.

The tau protein normally plays an important role in stabilizing microtubules in neurons, which are important for maintaining the structure of neurons and facilitating intracellular transport. The tau hypothesis proposed that abnormal phosphorylation of the tau protein, a major component of the neurofibrillary tangles found in the brains of individuals with AD and other neurodegenerative disorders, led to the formation of insoluble aggregates of tau proteins known as neurofibrillary tangles [9]. These tangles disrupted the normal functioning of neurons and eventually led to their death, resulting in the progressive cognitive impairment observed in AD. Both Aβ and hyperphosphorylated tau contributed to synaptic abnormalities in AD. As a result, modulating Aβ aggregation and ameliorating tau hyperphosphorylation are critical in treating AD. Studies reported the potentials of certain small molecules (e.g., methylene blue, aminothienopyridazines, rhodanines, idebenone, and memantine) [10], [11], [12], [13], monoclonal antibodies (e.g., aducanumab, ibrutinib, and bapineuzumab) [14], [15], [16], and natural products (e.g., curcumin, epigallocatechin-3-gallate, resveratrol, and berberine) [17], [18], [19], [20] in modulating Aβ aggregation or tau hyperphosphorylation. Still, few have been reported to exert effects through both pathways.

Heavy metal-based quantum dots (QDs) with intriguing emissive properties have long captured significant attention even prior to their recent recognition through the 2023 Nobel Prize in Chemistry [21]. More recently, photoluminescent carbon dots (CDs), including carbon nanodots (CNDs), graphene quantum dots (GQDs), carbon quantum dots (CQDs), and carbonized polymer dots (CPDs), prepared by the carbonization of small molecules have attracted great attention due to easy preparation, high diversity, good water solubility, and stability [22]. Due to their small size, unique optical properties, and high biocompatibility, they have gained much attention in various biomedical research fields, including drug delivery, cancer imaging and therapy, bioimaging, and biosensing [22]. CDs have been shown to inhibit Aβ aggregation [23], [24], [25] or tau aggregation [26], [27]. However, to the best of our knowledge, their effects on decreasing tau hyperphosphorylation have not been discussed in detail.

Much evidence showed that curcumin could inhibit Aβ aggregation and reduce hyperphosphorylation of tau protein [28], [29], [30], [31], [32], but the poor bioavailability of curcumin limited its application in medical use. The aim of the present study was to prepare water-soluble curcumin-derived CQDs (Cur-CQDs) using a green synthesis method that retained the beneficial effects of curcumin while addressing solubility issues. Cur-CQDs synthesized through a one-step dry heating process was found to exert dual effects on modulating Aβ aggregation and ameliorating tau hyperphosphorylation. In the present study, the as-prepared ammonia citrate-derived CQDs (AC-CQDs) and mannose-derived CQDs (MAN-CQDs) as controls was primarily intended to emphasize the importance of the source material, curcumin, in the synthesis of CQDs. By juxtaposing these with Cur-CQDs, we aimed to underscore the distinct characteristics and potential applications derived from this specific source material, thereby contributing to a more comprehensive understanding of the unique properties of Cur-CQDs. The influence on Aβ aggregation was evaluated by dot blot assay, thioflavin T assay, circular dichroism (CD), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), while SH-SY5Y cells were used as the model cells for the investigation of tau hyperphosphorylation.