There is strong evidence of a key role for cellular prion protein (PrPc), a protein that is associated with lipid rafts, as a receptor for oligomers of the Aβ peptide, resulting in the activation of a tyrosine-protein kinase (Fyn)-mediated complex signaling cascade leading to tau phosphorylation and Ca²⁺ dyshomeostasis [27]. Several studies support the idea that oligomers can interact with membranes through direct binding to GM1 [28,29]. This then results in the disruption of lipid bilayers, the alteration of their permeability and the malfunction of raft-associated Ca²⁺ channels, leading to Ca²⁺ influx into cells.

Although there is a variety of experiential evidence, the amyloid channel hypothesis still remains controversial. Indeed, numerous mechanisms can be responsible for the Aβ interaction with neuronal membranes causing the disruption of Ca²⁺ homeostasis. These include the activation of some type of cell surface receptor coupled to Ca²⁺ influx, and the alteration of membrane permeability [18,30]. Several reports showed that alterations in Ca²⁺ levels cause the dysfunction of voltage-gated calcium channels (VGCCs) [6], the downregulation of Ca²⁺ clearance mechanisms at the plasma membrane level [3,6] and the failure of Ca²⁺ homeostatic machinery located on intracellular organelles [5,6]. These events affected the maintenance of Ca²⁺ signals in old neurons, impairing learning and memory. It has been shown that Aβ can stimulate the opening of VGCCs, which, in turn, increases the intracellular concentration of Ca²⁺ [31]. In addition, the increase in intracellular Ca²⁺ levels can stimulate the overexpression of Ltype calcium channel subtype (Cav 1.2) in the hippocampal cell membranes of AD models, causing the influx of Ca²⁺ [32]. The inhibition of sarco-endoplasmic reticulum calcium transport ATPase (SERCA) as well as the release of Ca²⁺ via the ryanodine receptor (RyR) caused the increase in cytoplasmic Ca²⁺. This overloading caused the activation of β-secretase and thus an increased Aβ production and aggregation [33].

In the past few years, in vitro studies demonstrated that the Aβ peptide formed cation-selective pores into the plasma membrane, thus causing Ca²⁺ influx from the extracellular space across these Aβ pore-channels [34-37]. However, other in vivo studies showed that Aβ can improve the plasma membrane permeability to both anions and cations by altering its dielectric structure [38]. Following this evidence, numerous researchers have focused their attention on the effects of Aβ peptides on Ca²⁺ channels in neuronal cells. In particular, blocking Ca²⁺ influx was found to reduce the neurotoxicity of Aβ oligomers and the levels of insoluble Aβ1–40 and Aβ1–42 in the hippocampus of AD transgenic mice [39]. The increase in intracellular Ca²⁺ promotes the activation of calcineurin (CaN) and that of the phosphatases, including PP1, which is involved in long-term depression (LTD) [40]. CaN can contribute together with Aβ or tau to the loss of dendritic spines and synapses, leading to cognitive deficit in AD mouse models. Accordingly, CaN inhibitors can reverse or improve these impairments [41,42]. The Ca²⁺/calmodulin(CaM) complex activates the calmodulin dependent protein kinase II (CaMKII), playing an important role in memory formation and synaptic plasticity. Taking into account that many kinases can be activated by Ca²⁺, the dyshomeostasis of Ca²⁺ can increase tau phosphorylation [43-45]. Conversely, abnormal accumulation of intracellular tau can also induce Ca²⁺ overload, causing the dephosphorylation of calmodulin dependent protein kinase IV (CaMKIV) and cAMP response element binding protein (CREB) by activating CaN [41]. The increase in cytosolic Ca²⁺ can also activate JAK2-STAT1 signaling, leading to the binding of STAT1 to N-methyl D-aspartate receptors (NMDARs), and thus inhibits the transcription of specific GAS elements [43]; the increase in the cleaved STAT1 induced by tau also activates β-site amyloid precursor protein cleaving enzyme 1 (BACE1), promoting Aβ production [46]. All of these alterations reveal new mechanisms by which tau can induce synapse impairments and cognitive deficits. The presenilin proteins (PS1 and PS2) have also been implicated in the influx of Ca²⁺, as well as in the ER and mitochondrial Ca²⁺ signaling. Indeed, mutations in these proteins affect Ca²⁺ homeostasis [47].

An altered expression of calcium-binding (CBP) and calcium sensing proteins can modify the calcium-buffering capacity, causing the oversensitivity of neurons to glutamate released in the extracellular space [48-50]. In addition, the impairment of glutamate transporter function in the glial cell leads to the accumulation of glutamate in the synaptic cleft, activating the postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/NMDA receptors. Thus, Ca²⁺ entry in postsynaptic neurons disrupts the intracellular homeostasis and induces an increase in ROS production. Aβ has been reported to bind to NMDA and AMPA glutamate receptors [51], as well as nicotinic acetylcholine receptors [52], and all of these receptors are highly Ca²⁺-permeable. Furthermore, Aβ can influence VGCCs and the inositol 1,4, 5-trisphosphate receptor (IP₃R) [12]. Numerous research studies demonstrated that Aβ promotes the upregulation of VGCCs in different neuronal types, including cortical and hippocampal neurons [53]. In particular, Aβ peptides may over-activate the function of L-type VGCCs through a mechanism involving ROS production [54], or induce the overexpression of calcium channel subtypes (CaV1.2 and CaV1.3) in the hippocampus of AD transgenic mice [55] and in rat hippocampal neurons treated with Aβ [56]. The effects of Aβ on NMDARs have attracted considerable interest as these ligand-gated channels are involved in synaptic plasticity and long-term potentiation (LTP) [57]. Indeed, Aβ oligomers can induce the overactivation of NMDARs, resulting in a cytosolic Ca²⁺ increase [5, 21,25,58,59] through several mechanisms: by affecting glutamate availability [60,61] and/or by modifying NMDAR electrophysiological properties [62], or by changing membrane tension [63]. Importantly, the overactivation of GluN2B NMDAR subunits induced by Aβ [64] has been correlated to ER stress, to the depolarization and dysfunction of mitochondria [65,66], to microtubule disassembly and to a reduction in neurite length [64]. The synaptic activation of NMDAR is crucial for memory formation [67]. Hippocampal neurons showed differential expression of NMDA receptor subunits (NR1, NR2B) in AD-like rats [68]. In particular, the NR2B subunit, which is highly selective for Ca²⁺ transport and is known to play a decisive role in Ca²⁺-induced apoptosis, was overexpressed in AD models compared to controls [68]. The persistent overactivation of the NMDA receptor in the postsynaptic terminal stimulates hippocampal neurons, which allows higher calcium influx resulting in excitotoxicity. The Aβ-induced activation of NMDAR promoted its endocytosis [69]. We have recently observed that lysophosphatidylcholine and arachidonic acid, which cause membrane compression and stretch, respectively, can activate NMDAR and AMPAR through a change in membrane tension induced by Aβ oligomers [63]. In particular, lysophosphatidylcholine is able to neutralize the oligomer-induced activation of the NMDA receptors, whereas arachidonic acid activates the receptors similarly to the oligomers with no additive effects, suggesting that Aβ-induced toxicity can also be caused by the perturbation of the mechanical properties of lipid membranes sensed by NMDA and AMPA receptors [63]. Memantine, an NMDAR antagonist, was approved in 2002 as a therapeutic drug in moderate to severe AD [70,71]. However, other potential drugs targeting NMDARs are not included in AD therapy because of their intolerable side effects.

Endoplasmic-Reticulum and Mitochondrial Calcium Dysregulation

As reported above, Aβ peptides are able to induce a high release of Ca²⁺ from the ER, thus promoting the activation of the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress [72,73]. Notably, Aβ oligomers may disrupt ER Ca²⁺ homeostasis indirectly by the increase in Ca²⁺ influx from the extracellular space, which in turn triggers Ca²⁺ release from intracellular stores [74], or directly by interacting with several regulators of ER Ca²⁺, such as RyR and I₃PR [75-80]. On the other hand, ER Ca²⁺ dyshomeostasis causes abnormal Aβ production and neuronal apoptosis [81-83]. In addition, IP₃R was found to modulate Ca²⁺ homeostasis in AD [84] and its alterations have been detected in cells derived from AD patients since 1994 [85,86].

Mitochondria play a key role in the modulation of intracellular Ca²⁺ signaling [87]. Indeed, they can quickly resume Ca²⁺ to prevent Ca²⁺ overload into the cytosol, activating the Ca²⁺-dependent mitochondrial matrix dehydrogenase to produce ATP. However, this disruption of mitochondrial Ca²⁺ regulation affects energy production and oxidative stress, resulting in mitochondrial dysfunction [88]. In particular, the excessive Ca²⁺ influx into the mitochondria induces mitochondrial outer membrane permeabilization and the subsequent release of pro-apoptotic factors into the cytoplasm, including cytochrome C and apoptosis-inducing factor, which activate apoptosis cell death [89] (Figure 1). Mitochondrial dysfunction has been proposed as an early event in AD and other aging-related neurodegenerative disorders [90]. Studies on brains from AD patients and AD mouse models showed impaired mitochondrial function, associated with decreased bioenergetics and ATP synthesis [91], morphological abnormalities [92], the imbalance of mitochondrial dynamics [93] and the redistribution of mitochondria [94]. Synapses are particularly rich in mitochondria, which provide energy for Ca²⁺ homeostasis. In addition, synaptic mitochondria are more sensitive to Ca²⁺ dyshomeostasis with respect to non-synaptic mitochondria [95]. During LTP, microtubule associated protein 1B (MAP1B) phosphorylation and local concentrations of CaMKII were increased [96]. CaMKII is responsible for phosphorylating MAP2, which enhances synaptic response [97]. The accumulation of tau impairs synapses and memory by activating Ca²⁺-dependent CaN and suppressing nuclear CaMKIV/CREB signaling, thus revealing a new mechanism by which tau can induce synaptic toxicity [41]. In vitro studies have reported that Aβ oligomers induce mitochondrial Ca²⁺ uptake [98,99] and Ca²⁺ transfer from the ER to mitochondria [100] in cultured rat primary neurons, even if the in vivo mechanism remains unknown. A recent study showed that the increase in Ca²⁺ levels in neuronal mitochondria of transgenic mice appeared only after plaque deposition and before neural death [101]. This mitochondrial Ca²⁺ overload involves toxic extracellular Aβ oligomers and requires the mitochondrial Ca²⁺ uniporter. The authors propose a novel potential therapeutic target for AD through the blocking of the mitochondrial Ca²⁺ uniporter that was found to reduce mitochondrial Ca²⁺ overload [101].

Various studies have observed that the increase in Ca²⁺ levels in the ER caused the leakage of Ca²⁺ into the cytoplasmic compartment, affecting the mitochondrial calcium homeostasis [8,102]. Recently, an interesting hypothesis has been proposed about the role of mitochondria-associated ER membrane (MAM), the lipid raft-like domain of the ER closely opposed to mitochondria, in AD pathogenesis [103]. As already mentioned, MAM is involved in several important mechanisms, including calcium transport, the synthesis of phospholipids, mitochondrial fission and fusion, the division of mtDNA, and cholesterol esterification [104]. Thus, several studies have been investigating the role of mitochondrial dysfunction mediated by Aβ and MAM, underlying its putative role in AD.

Concluding Remarks

Many studies have revealed that the perturbation of Ca²⁺ homeostasis is an early event in the cascade of neuronal alterations underlying the cytotoxicity induced by misfolded Aβ aggregates and hyperphosphorylated tau. However, so far, no common consensus has been reached on the molecular mechanisms of neuronal Ca²⁺ overload, causing the remodeling of signaling pathways with excitotoxicity and memory dysfunction in AD. The effects of Aβ on NMDARs have attracted considerable interest as these ligand-gated channels are involved in synaptic plasticity and LTP. Importantly, the over-activation of GluN2B NMDAR subunits induced by Aβ has been correlated to ER stress and to the depolarization and dysfunction of mitochondria. Recently, ER and mitochondrial Ca²⁺ dyshomeostasis have also been proposed as early causative events in AD.

The main unsolved issue is whether the neuronal Ca²⁺ alterations caused by Aβ extracellular deposits could be non-specific, involving just lipid membrane components, or specific by membrane receptors and other cell surface proteins. There is strong evidence of a key role for PrPc, associated with lipid rafts, as a receptor for Aβ oligomers, resulting in the activation of a Fyn-mediated complex signaling cascade, leading to tau phosphorylation and loss of Ca²⁺ homeostasis. However, the data reported in several other studies support the idea that Aβ oligomers can interact with membranes through direct binding to GM1. This then results in the disruption of lipid bilayers, the alteration of their permeability and the misfunction of raft-associated Ca²⁺ channels, leading to Ca²⁺ influx into cells. These findings do not necessarily contradict the view that PrPc behaves as a receptor of a class of Aβ oligomers. Considering the existence of many structurally distinct conformers, different Aβ aggregates could interact with PrPc and GM1 with different affinities. It is increasingly evident that toxicity is not a feature that is inherent to a given type of misfolded protein oligomer, but is instead a property that emerges from the complex interplay between the structural features of oligomers and the lipid composition of the neuronal membranes. Trodusquemine, a natural product in the aminosterol class, was recently shown to prevent Aβ toxicity by displacyng the aggregates from the cell membranes, suggesting that molecules that interact directly with cell membranes, rather than binding oligomeric aggregate themselves, could represent a useful approach in the treatment of AD.

Overall, the question of the molecular basis of Ca²⁺ perturbation in AD pathophysiology needs further investigations for the development of targeted therapies for AD. Memantine, an NMDAR antagonist approved in 2002 as a therapeutic drug in moderate to severe AD, appears to be promising in AD therapy, together with other potential drugs targeting NMDARs and PrPc. However, according to the latest evidence that both Aβ and tau pathologies have synergistic effects, the most efficacious approach to slow AD may be to combine anti-Aβ and anti-tau therapies.

Author Contributions: Writing, reviewing, and editing, R.C. and C.C.; conceptualization and supervision, R.C. and C.C.; both authors have read and agreed to the published version of the manuscript.

Funding: This research was funded by the University of Florence (Fondi Ateneo) and by the Ministry of Education, Universities and Research of Italy (Progetto Dipartimento di Eccellenza “Gender Medicine”).

Conflicts of Interest: The authors declare no conflict of interest.

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