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MHDIs-Mediated Amelioration of Aβ-Induced Synaptic Dysfunction: Comparison
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Please note this is a comparison between Version 3 by Amina Yu and Version 2 by Amina Yu.

Medicinal herbs and their derived ingredients (MHDIs) have multitarget and multichannel properties, engendering exceptional AD treatment outcomes. In the brain, the mammalian target of rapamycin plays a major role in dendritic growth and synaptic plasticity development. Synaptic activity is essential in synaptic plasticity and memory formation, and maintenance of synaptic activity effectively protects against Alzheimer’s disease (AD) pathogenesis. The maintenance of normal synaptic plasticity requires particular proteins, including immediate early genes (IEG) and activity-regulated cytoskeleton-associated protein (Arc), which are crucial for long-term memory formation and consolidation. Synaptic plasticity disruption followed by synapse loss caused by Aβ oligomers in the hippocampal CA1 subregion occurs in the early stages of AD, and the hippocampal CA1 subregion is more vulnerable to AD-related neuronal damage than are the other subregions. In addition, synapse loss and dendritic spine abnormalities are closely associated with cognitive decline. Herein, the focus is

  • Aβ plague
  • medicinal herb
  • synaptic dysfunction

1. Involvement of Synaptic Protein Expression in Aβ-Induced Synaptic Dysfunction

The synapse-associated proteins, involving presynaptic dynamin 1, synapsin-1 (SYN-1), synaptophysin (SYP), postsynaptic density protein (PSD)-95, and neural cell adhesion molecule, play a crucial role in synaptic plasticity and memory formation [1][2]. SYN-1, a presynaptic marker, is significantly expressed in synaptic vesicles, and it plays a crucial role in the modulation of neurotransmitter release [3]. SYN-1 expression can reflect synapse density [4]. Moreover, SYP, a calcium-binding protein, is a presynaptic vesicle protein, with a role in synaptic formation and vesicular endocytosis [3][5]. PSD-95, a critical scaffolding component of postsynaptic terminals, is vital for synaptic transmission and synaptic stabilization during long-term potentiation (LTP) [6][7]. Dendritic spine density is also crucial for synaptic function and cognitive behavior [8]. Microtubule-associated protein 2 (MAP-2), a dendritic marker, is a pivotal factor for dendritic spine development and dendritic elongation. Thus, upregulated MAP-2 expression exerts beneficial effects against synaptic dysfunction through dendritic morphology maintenance in Aβ-damaged neurons [2]. By contrast, activation of RhoA, a member of the Rho–GTPase family, and its downstream target ROCK reduces dendritic spine density and length during AD pathogenesis [9]. Moreover, the accumulation of p-tau in the hippocampus reduces MAP-2 expression, leading to cognitive dysfunction [10]. APP also has critical physiological roles in dendritic spine density and synaptic plasticity [11]. Protein kinase c (PKC)/BDNF-mediated signaling plays a key role in synaptogenesis, synapse development, synaptic transmission, and synaptic plasticity in the hippocampus and the related cortical regions in AD animal models [2][6]. PKC plays an essential role in the modulation of the survival and apoptotic pathways. Moreover, BDNF is essential for cognitive function through the regulation of axonal sprouting and synaptic plasticity [12].

2. Effects of Medicinal Herbs and Their Derived Ingredients (MHDIs) on Aβ-Induced Synaptic Dysfunction through Synaptic Protein Expression Regulation

In 2014, Zhan et al. reported that berberine rescues synaptic/memory deficits by upregulating IEG and Arc mRNA and protein levels in the hippocampus at 7 weeks after D-galactose-induced AD [13]. Xanthoceras sorbifolia extract increases dendritic spine density probably through the activation of brain-derived neurotrophic factor (BDNF)/TrkB/PSD-95-mediated signaling and inhibition of RhoA/ROCK-mediated signaling in the hippocampus at 18 days after Aβ25–35-induced AD [9]. In 2017, Ji et al. reported that daucosterol palmitate, extracted from Alpinia oxyphylla Miq., ameliorates Aβ-induced cognitive impairment partly due to the enhancement of SYP expression in the hippocampus at 14 days after Aβ1–42-induced AD [5]. Catalpol, extracted from Rehmanniae Radix, effectively promotes the expression of synaptic proteins including dynamin 1, SYP, PSD-95, and MAP-2 by activating PKC/BDNF-mediated signaling in the hippocampus at 2 months in aged rats [2]. BDNF combines with its receptor TrkB to activate Akt/cyclic AMP response element-binding protein (CREB)-mediated signaling. Akt is the upstream regulator of CREB, which plays a key role in the maintenance of synaptic plasticity during the pathogenesis of AD [14]. However, Aβ accumulation can suppress the proteolytic cleavage of pro-BDNF, which reduces the BDNF levels [15]. Icariin, isolated from Epimedium brevicornum Maxim, attenuates Aβ-induced synaptic dysfunction through the activation of BDNF/TrkB/Akt/CREB-mediated signaling in the hippocampus at 28 days after Aβ1–42-induced AD [14]. In addition, molecular chaperones exhibit diverse functions such as protein folding and Aβ disaggregation. Thus, chaperone proteins protect against Aβ-induced synaptic injury in the hippocampal and cortical neurons by preventing Aβ oligomers binding to the dendrites [7].

3. Involvement of Acetylcholine Release in Aβ-Induced Synaptic Dysfunction

Cholinergic neurons that release acetylcholine (ACh) from axon terminals are most closely associated with cognitive function; therefore, loss of cholinergic neurons causes memory and learning deficits [16][17]. ACh synthesis and degradation require choline acetyltransferase (ChAT) and AChE, respectively. Thus, brain ACh levels can be increased by promoting ChAT function or reduced by upregulating AChE activity [18]. Aβ accumulation alters neurotransmitter-related enzyme expression and thus increases AChE activity but reduces ChAT activity, resulting in reduced synaptic transmission and plasticity [19][20]. Increased AChE levels, in turn, trigger Aβ aggregation, leading to exacerbation of Aβ accumulation [20]. In the early stages of AD, ACh neuromediator synthesis is reduced [21].

4. Effects of MHDIs on Aβ-Induced Synaptic Dysfunction through ChAT, ACh, and AChE Level Regulation

Galantamine, a phenanthrene alkaloid isolated for the first time from Galanthus woronowii [22], is the first nutraceutical to be approved by the United States Food and Drug Administration as a reversible AChE inhibitor [23]. Moreover, galantamine can block ACh degradation in the synaptic cleft, resulting in constant ACh stimulation of cholinergic receptors [23][24]. In 2006, Meunier et al. demonstrated that galantamine protects against Aβ-induced memory deficits partly by inhibiting AChE activity in the hippocampus at 7 days after Aβ25–35-induced AD [25]. Galantamine also acts as an allosteric modulator of nicotinic ACh receptors (nAChRs) [26][27]. Galantamine enhances microglial Aβ clearance partly by upregulating microglial α7 nAChR expression in the hippocampus at 2 weeks after Aβ42-induced AD [26]. It has been suggested that AChE plays a key role in Aβ accumulation in the early stages of senile plaque formation [28]. In 2022, Siddique et al. reported that galantamine effectively inhibits Aβ42 aggregation mainly by reducing AChE activity and promoting GSH-Px levels in the brain at 57 days in the transgenic Drosophila model of AD [28]. Currently, galantamine provides beneficial effects on mild to moderate AD by downregulating AChE activity and upregulating ACh release in the brain [29]. However, galantamine can cause some adverse effects, such as hepatotoxicity and gastrointestinal disorders, and cannot reduce the rate of decline of cognitive capacities in the later stages of AD [24][30]. Gastrodia elata Blume treatment significantly improves spatial memory mainly by upregulating ChAT expression and downregulating AChE expression in the prefrontal cortex and hippocampus at 52 days after Aβ25–35-induced AD [20]. In 2014, Huang et al. reported that bajijiasu ameliorates Aβ-induced cognitive dysfunction partly through increased ACh levels and decreased AChE levels in the hippocampus at 25 days after Aβ25–35-induced AD [31]. Lychee seed extract improves cognitive dysfunction probably by inhibiting Aβ, tau, and AChE formation in the hippocampus at 8 weeks in a rat model of T2DM and AD [32]. In 2018, Zang et al. observed that GJ-4 improves cognitive ability partly by downregulating AChE levels and upregulating ACh levels in the cortex and hippocampus at 10 days after Aβ25–35-induced AD [33]. Lignans, isolated from S. chinensis Baill, ameliorate cognitive decline partly through the upregulation of ACh levels in the brain at 1 week in AD rats [16].

5. Involvement of Postsynaptic Receptor and Protein Expression in Aβ-Induced Synaptic Dysfunction

NMDARs (NRs) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicaci (AMPA) receptors (AMPARs), both belonging to ionotropic glutamate receptors, play multiple roles in synaptic plasticity and excitotoxicity [34]. NMDAR and AMPAR [including glutamate A1 (GluA1) and GluA2 subunits] are the major components of PSD, and these receptors can regulate excitatory synaptic connections and maintenance process of LTP [4]. NMDARs are ligand-gated ion channels and their subtypes, such as NR1/NR2A (NMDAR2A) and NR1/NR2B (NMDAR2B), are regulated in the synaptic transmission process [34][35]. Ca2+/calmodulin (CaM)-dependent kinase II (CaMKII), a multifunctional serine/threonine protein kinase, is a pivotal enzyme in Ca2+/CaM-mediated signaling. CaMKII isoforms are derived from four genes (α, β, γ, and δ), and CaMKIIα is important for learning and memory [36]. Under physiological conditions, NMDAR, CaMKII, and PKC in postsynaptic density are important in synaptic plasticity [37][38]. Intracellular calcium ions phosphorylate CaMKII, which subsequently activates downstream ERK/CREB-mediated signaling for the induction of LTP in the hippocampus [36]. By contrast, in AD pathogenesis, Aβ deposition triggers extracellular Ca2+ flow into the cytoplasm, ultimately leading to calcium overload. This calcium overload subsequently causes neurotoxicity, reducing the expression of AMPAR 1 (GluA1), CaMKII, PKC, and NR2B contained in NMDARs [4][38][39]. Thus, Aβ accumulation disturbs NMDAR-associated LTP induction by affecting NR2A/NR2B ratio in the hippocampal CA1 and dentate gyrus [34], whereas synaptic NMDAR activation causes neuroprotective effects on Aβ intraneuronal accumulation through the enhancement of synaptic activity and plasticity [40].

6. Effects of MHDIs on Aβ-Induced Synaptic Dysfunction through Postsynaptic Receptor and Protein Expression Regulation

In 2013, Wei et al. reported that β-asarone, isolated from Acori graminei Rhizoma, effectively alleviates cognitive decline by activating CaMKIIα/CREB-mediated signaling in the frontal cortex at 4 months in APP/PS1 mice [41]. Oleanolic acid, from Ligustrum lucidum, ameliorates Aβ-induced memory deficit partly by upregulating NMDAR2B, CaMKII, and PKC expression in the hippocampus at 28 days after Aβ25–35-induced AD [38]. However, in 2012, Liu et al. reported that pathological cytoplasmic calcium overload occurs through the activation of NR1 subunits of NMDARs. Overloaded Ca2+ combines with CaM to subsequently elicit increased CaMKII phosphorylation, and this in turn promotes NR1 expression; this creates a vicious cycle between the NR1 and CaMKII expression, causing neuronal cell death in the hippocampal CA1 region [34].

7. Summary

MHDIs mentioned herein reduce Aβ-induced synapse loss and promote synaptic proteins including dynamin 1, SYP, PSD-95, and MAP-2 by activating BDNF/Akt/CREB-mediated signaling in the hippocampus. Moreover, they ameliorate synaptic transmission deficits mainly through the upregulation of ACh PKC, NR2B, and CaMKII expression and downregulation of AChE expression in the hippocampus in the early and late phases of AD in animal models.

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