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![A schematic diagram illustrating the impact of lactate on the CNS of AD patients. Lactate, a product of glycolysis, is an essential substrate for maintaining normal brain energy metabolism. Mitochondria, the "energy factories" in neurons, rely not only on glucose to produce ATP but also require astrocytes to provide "raw materials" such as lactate. Lactate produced by glycolysis in astrocytes can enter mitochondria for further oxidation, ultimately converting into CO2 and water. Astrocytes, the most abundant glial cells, play a crucial role in supporting neuronal energy demands. In the brain, lactate produced via glycolysis or stored glycogen (glycogenolysis) is released from astrocytes through monocarboxylate transporter 4 (MCT4). It is then absorbed by neurons via monocarboxylate transporter 2 (MCT2) on the neuronal membrane [34]. This lactate, after being converted to pyruvate, is oxidized by neuronal mitochondria. Thus, the described "astrocyte-neuron lactate shuttle hypothesis" is activated under aerobic conditions, where neuronal glutamatergic synaptic activity promotes lactate production in astrocytes, and astrocytes supplement the basal ATP production of neurons, typically derived from glucose carbon oxidation directly from neuronal glycolysis [35].
Under low glucose conditions, lactate glycogenolysis in astrocytes may be upregulated to meet neuronal demands. Lactate shuttling and carbon supply to neurons can be disrupted by various processes, including: downregulation of glucose transporters across the BBB leading to a general reduction in glucose uptake, decreased expression of hexokinase, and altered expression of astrocytic MCT4 and neuronal MCT2 during aging. In addition to this, the brain can also utilize lactate transported from other organs via the bloodstream. As early as the 1970s and 1980s, numerous researchers had already discovered that lactate could be "shuttled" between various groups.
In studies on improving cognitive dysfunction in AD patients, restoring mitochondrial function is considered a very effective approach. Current research has found that lactate is not only a "signaling molecule" but can also affect protein structure. In Lian et al.'s study on PD, it was found that SIRT1 can affect lactate homeostasis. They pointed out that excessive lactate accumulation in the brain can exacerbate the pathological features of PD, while deacetylation of pyruvate kinase M2 (PKM2) at K135 and K206 by SIRT1 to block its enzymatic activity, inhibiting glycolysis to reduce lactate production, alleviated PD [38]. SIRT1 also has a role in regulating mitochondrial dynamics. SIRT1 is a NAD+-dependent deacetylase mainly located in the nucleus, and elevated NAD levels in the body activate SIRT1 [39]. SIRT1 has been shown to improve mitochondrial oxidative metabolism and actively regulate autophagy and mitochondrial function under oxidative stress [40-42]. In some studies, SIRT1 has been shown to be involved in the clearance of Aβ and Tau proteins, and its deacetylation function has the following effects: first, the transcription factor](/_next/image?url=https%3A%2F%2Fpub-8c0ddfa5c0454d40822bc9944fe6f303.r2.dev%2Fai-drawings%2FcKA9jejJMp5uNe7lVgVtEuItcdsfIJvV%2F1a951d3f-b53e-440c-9f46-f23a03d0add4%2F2f94c1e2-dfcb-42c6-a2be-283de804b398.png&w=3840&q=75)
Schematic Title: Schematic Diagram of Microneedle Patch Preparation Process Overall Style and Layout: Style: Simple, modern, with technological line illustrations or flat vector graphics. Use a refreshing color scheme, mainly blue, gray, and white, with key parts highlighted in orange or green. Layout: A horizontal flowchart from left to right, including 4 core steps. Each step is clearly marked with a numbered module (Step 1-4). Detailed Description of Steps: Step 1: Mold Casting Scene: On the left is a transparent/translucent polymer microneedle mold (such as a PDMS mold), with a regularly arranged array of inverted pyramid or conical pits visible on its surface. Action: A pipette or dropper is dropping a drop of viscous, translucent mixed solution onto the surface of the mold. The solution can be symbolically dotted with tiny nanoparticles (NPs) to represent DNase-PDA@C-176 NPs. Label: Label the solution as "HA and DNase-PDA@C-176 NPs mixed solution". Label the mold as "Microneedle Mold". Step 2: Vacuum Filling Scene: The mold is placed in a transparent vacuum chamber. State: The solution on the surface of the mold has spread and covered the entire mold area. A vacuum pump icon (or a simple downward arrow indicating air extraction) is connected above the vacuum chamber. Key Visual: In the pits of the mold, use an enlarged partial cross-sectional view to show that the solution is being drawn down under the action of vacuum negative pressure, completely filling every tiny corner of the pit and expelling all air bubbles. A few small upward air bubble arrows can be used to indicate the dynamic process of exhaust. Label: "Vacuum Filling" or "Vacuum Degassing". Step 3: Drying and Curing Scene: The mold is transferred to a dry environment, such as being placed under a gentle warm air flow (indicated by curved arrows) or placed in a "drying oven" icon. State: The moisture in the solution in the mold evaporates, the volume shrinks, and finally solid needles are formed in the mold pits. A partial cross-sectional view can be used again to compare: from pits filled with liquid to solid needles. Label: "Drying/Curing". Step 4: Demolding and Finished Product Action: A hand or a robotic arm is carefully peeling/removing a formed microneedle patch substrate (a transparent polymer backing) from below. Finished Product Display: The peeled patch is displayed completely. Hundreds of tiny conical needle tips stand neatly on the patch substrate, forming a perfect array. Multi-angle Display (Optional): Main View: Complete patch. Side View/Magnified View: Shows the sharp needle tip and complete shape of a single microneedle, with dimensions labeled as "Height: 1000 μm, Base Width: 600 μm". Top View (Illustration): Shows the regular arrangement of microneedles, such as a "10x10 array" or similar. Final Label: Label the finished product as "DNase-PDA"
A schematic diagram illustrating the impact of lactate on th...
