Ca2＋失调与阿尔茨海默病发生发展关系的研究进展

阿尔茨海默病（Alzheimer’s disease,AD）是全球老年人中最常见的神经退行性疾病。在对家族性AD的动物模型和个别AD患者死后脑组织的研究中发现,除了A1342水平升高外,神经元内Ca2＋信号失调,并且Ca2＋信号蛋白表达水平也发生了改变。淀粉样蛋白斑、神经元纤维缠结和神经元丢失是AD的后期标志,它们的共同点可能是破坏神经元钙离子信号。细胞内钙离子水平提高在功能上与淀粉样蛋白斑、早老素突变、tau缠结和突触功能障碍相关,基于这些研究,产生了AD的Ca2＋假说。主要介绍神经元内Ca2＋失调与AD的关系以及钙拮抗剂作为AD的潜在治疗方法。     

Mechanisms of amyloid beta protein-induced modification in ion transport systems: implications for neurodegenerative diseases

1. Alzheimer's disease (AD) is a neurodegenerative disorder that affects the cognitive function of the brain. Pathological changes in AD are characterized by the formation of amyloid plaques and neurofibrillary tangles as well as extensive neuronal loss. Abnormal proteolytic processing of amyloid precursor protein (APP) is the central step that leads to formation of amyloid plaque, neurofibrillary tangles, and neuronal loss.2. The plaques, which accumulate extracellularly in the brain, are composed of aggregates and cause direct neurotoxic effects and/or increase neuronal vulnerability to excitotoxic insults. The aggregates consist of soluble pathologic amyloid beta peptides AP[1–42] and AP[1–43] and soluble nonpathologic AP[1–40]. Both APP and AP interact with ion transport systems. AP induces a wide range of effects as the result of activating a cascade of mechanisms.3. The major mechanisms proposed for AP-induced cytotoxicity involve the loss of Ca²⁺ homeostasis and the generation of reactive oxygen species (ROS). The changes in Ca²⁺ homeostasis could be the result of (1) changes in endogenous ion transport systems, e.g. Ca²⁺ and K⁺ channels and Na⁺/K⁺-ATPase, and membrane receptor proteins, such as ligand-driven ion channels and G-protein-driven releases of second messengers, and (2) formation of heterogeneous ion channels.4. The consequences of changes in Ca²⁺-homeostasis-induced generation of ROS are (a) direct modification of intrinsic ion transport systems and their regulatory mechanisms, and (b) indirect effects on ion transport systems via peroxidation of phospholipids in the membrane, inhibition of phosphorylation, and reduction of ATP levels and cytoplasmic pH.5. We propose that in AD, AP with its different conformations alters cell regulation by modifying several ion transport systems and also by forming heterogeneous ion channels. The changes in membrane transport systems are proposed as early steps in impairing neuronal function preceding plaque formation. We conclude that these changes damage the membrane by compromising its integrity and increasing its ion permeability. This mechanism of membrane damage is not only central for AD but also may explain other malfunctioned protein-processing–related pathologies.     

Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

Alzheimer's disease (AD) is an age‐related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD‐504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLP^APT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient‐derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau‐interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLP^APT mice.     

Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the ‘amyloid hypothesis’ of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca²⁺) handling and may contribute to AD pathogenesis, an idea termed the ‘calcium hypothesis’ of AD. Mutations in presenilin proteins account for the majority of FAD cases. Presenilins function as catalytic subunits of γ-secretase involved in the generation of Aβ peptide. Recently, we discovered that presenilns function as low-conductance, passive ER Ca²⁺ leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins results in the loss of ER Ca²⁺ leak function activity and Ca²⁺ overload in the ER. These results provided potential explanation for abnormal Ca²⁺ signaling observed in FAD cells with mutations in presenilns. The implications of these findings for understanding AD pathogenesis are discussed in this article.     

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

Alzheimer disease (AD), the leading cause of dementia, is characterized by the accumulation of β-amyloid peptides (Aβ) in senile plaques in the brains of affected patients. Many cellular mechanisms are thought to play important roles in the development and progression of AD. Several lines of evidence point to the dysregulation of Ca²⁺ homeostasis as underlying aspects of AD pathogenesis. Moreover, direct roles in the regulation of Ca²⁺ homeostasis have been demonstrated for proteins encoded by familial AD-linked genes such as PSEN1, PSEN2, and APP, as well as Aβ peptides. Whereas these studies support the hypothesis that disruption of Ca²⁺ homeostasis contributes to AD, it is difficult to disentangle the effects of familial AD-linked genes on Aβ production from their effects on Ca²⁺ homeostasis. Here, we developed a system in which cellular Ca²⁺ homeostasis could be directly manipulated to study the effects on amyloid precursor protein metabolism and Aβ production. We overexpressed stromal interaction molecule 1 (STIM1) and Orai1, the components of the store-operated Ca²⁺ entry pathway, to generate cells with constitutive and store depletion-induced Ca²⁺ entry. We found striking effects of Ca²⁺ entry induced by overexpression of the constitutively active STIM1_D76A mutant on amyloid precursor protein metabolism. Specifically, constitutive activation of Ca²⁺ entry by expression of STIM1_D76A significantly reduced Aβ secretion. Our results suggest that disruptions in Ca²⁺ homeostasis may influence AD pathogenesis directly through the modulation of Aβ production.     

脑锌代谢与阿尔茨海默病

锌是中枢神经系统含量最丰富的过渡金属元素之一,对维持中枢神经系统正常生理功能具有重要作用,其稳态失衡与多种疾病有关。阿尔茨海默病是一种多病因神经退行性疾病,以β-淀粉样斑块形成和神经原纤维缠结为主要病理特征。研究表明,脑锌代谢紊乱在阿尔茨海默病发病过程中扮演重要角色,但确切机制尚不十分清楚。综述了脑锌代谢和稳态调控以及锌和锌转运蛋白参与β-淀粉样蛋白沉积与老年斑形成的病理过程,并探讨了金属一蛋白阻尼复合物如何通过恢复脑锌稳态延缓疾病进程、改善患者认知能力的治疗策略。     

Cellular cholesterol homeostasis and Alzheimer's disease: Thematic Review Series: ApoE and Lipid Homeostasis in Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid-β (Aβ) peptides (especially Aβ1-42) and neurofibrillary tangles, composed of hyperphosphorylated tau and accompanied by chronic neuroinflammation. Aβ peptides are derived from the amyloid precursor protein (APP). The oligomeric form of Aβ peptides is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques. ApoE is the major apolipoprotein of the lipoprotein(s) present in the CNS. ApoE has three alleles, of which the Apoe4 allele constitutes the major risk factor for late-onset AD. Here we describe the complex relationship between ApoE4, oligomeric Aβ peptides, and cholesterol homeostasis. The review consists of four parts: 1) key elements involved in cellular cholesterol metabolism and regulation; 2) key elements involved in intracellular cholesterol trafficking; 3) links between ApoE4, Aβ peptides, and disturbance of cholesterol homeostasis in the CNS; 4) potential lipid-based therapeutic targets to treat AD. At the end, we recommend several research topics that we believe would help in better understanding the connection between cholesterol and AD for further investigations.     

Convergence of Amyloid-β and Tau Pathologies on Mitochondria In Vivo

The histopathological characteristics of Alzheimer’s disease (AD) are amyloid-β (Aβ) containing plaques and neurofibrillary tangles (NFTs) as well as neuronal and synaptic loss. Until today, the underlying mechanisms of the interplay of plaques and tangles remained unresolved. There is increasing evidence that mitochondrial dysfunction might be a possible link, as revealed by studies in several APP and tau transgenic mouse models. Recently, we examined mitochondrial function in a novel triple transgenic mouse model (pR5/APP/PS2)—^tripleAD mice—that combines both pathologic features of the disease in brain. Using comparative, quantitative proteomics (iTRAQ) and mass spectroscopy, we found a massive deregulation of 24 proteins, of which one third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Remarkably, deregulation of complex I was related to tau, whereas deregulation of complex IV was Aβ dependent, both at the protein and activity levels. The ^tripleAD mice showed synergistic effects of Aβ and tau already at the age of 8 months, resulting in a depolarized mitochondrial membrane potential. At 12 months, the strongest defects on OXPHOS, synthesis of ATP and reactive oxygen species, were exhibited in the ^tripleAD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in impairing mitochondria. This review highlights the convergence of Aβ and tau on mitochondria and establishes a molecular link in AD pathology in vivo.     

Oxidative stress in Alzheimer disease

Alzheimer disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress (e.g., protein oxidation, lipid oxidation, DNA oxidation and glycoxidation) during the course of the disease. Advanced glycation endproducts (AGEs) are present in amyloid plaques in AD, and its extracellular accumulation may be caused by an accelerated oxidation of glycated proteins. AGEs participate in neuronal death causing direct (chemical) and indirect (cellular) free radical production and consequently increase oxidative stress. The development of drugs for the treatment of AD that breaks the vicious cycles of oxidative stress and neurodegeneration offer new opportunities. These approaches include AGE-inhibitors, antioxidants and anti-inflammatory substances, which prevent free radical production.Key words: ageing, advanced glycation endproducts, Alzheimer disease, amyloid, oxidative stress     

Dysregulation of Calcium Homeostasis in Alzheimer’s Disease

The accumulation of oligomeric species of β-amyloid protein in the brain is considered to be a key factor that causes Alzheimer’s disease (AD). However, despite many years of research, the mechanism of neurotoxicity in AD remains obscure. Recent evidence strongly supports the theory that Ca²⁺ dysregulation is involved in AD. Amyloid proteins have been found to induce Ca²⁺ influx into neurons, and studies on transgenic mice suggest that this Ca²⁺ influx may alter neuronal excitability. The identification of a risk factor gene for AD that may be involved in the regulation of Ca²⁺ homeostasis and recent findings which suggest that presenilins may be involved in the regulation of intracellular Ca²⁺ stores provide converging lines of evidence that support the idea that Ca²⁺ dysregulation is a key step in the pathogenesis of AD. Special issue article in Honor of Dr. Graham Johnston.     

An aluminum-based rat model for Alzheimer's disease exhibits oxidative damage, inhibition of PP2A activity, hyperphosphorylated tau, and granulovacuolar degeneration

In Alzheimer's disease (AD), oxidative damage leads to the formation of amyloid plaques while low PP2A activity results in hyperphosphorylated tau that polymerizes to form neurofibrillary tangles. We probed these early events, using brain tissue from a rat model for AD that develops memory deterioration and AD-like behaviors in old age after chronically ingesting 1.6 mg aluminum/kg bodyweight/day, equivalent to the high end of the human dietary aluminum range. A control group consumed 0.4 mg aluminum/kg/day. We stained brain sections from the cognitively-damaged rats for evidence of amyloid plaques, neurofibrillary tangles, aluminum, oxidative damage, and hyperphosphorylated tau. PP2A activity levels measured 238.71+/-17.56 pmol P(i)/microg protein and 580.67+/-111.70 pmol P(i)/microg protein (p<0.05) in neocortical/limbic homogenates prepared from cognitively-damaged and control rat brains, respectively. Thus, PP2A activity in cognitively-damaged brains was 41% of control value. Staining results showed: (1) aluminum-loading occurs in some aged rat neurons as in some aged human neurons; (2) aluminum-loading in rat neurons is accompanied by oxidative damage, hyperphosphorylated tau, neuropil threads, and granulovacuolar degeneration; and (3) amyloid plaques and neurofibrillary tangles were absent from all rat brain sections examined. Known species difference can reasonably explain why plaques and tangles are unable to form in brains of genetically-normal rats despite developing the same pathological changes that lead to their formation in human brain. As neuronal aluminum can account for early stages of plaque and tangle formation in an animal model for AD, neuronal aluminum could also initiate plaque and tangle formation in humans with AD.     

Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis

Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the ‘amyloid hypothesis’ of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca²⁺) handling and may contribute to AD pathogenesis, an idea termed the ‘calcium hypothesis’ of AD. Mutations in presenilin proteins account for majority of FAD cases. Presenilins function as catalytic subunit of γ-secretase involved in generation of Aβ peptide Recently, we discovered that presenilns function as low-conductance, passive ER Ca²⁺ leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins result in loss of ER Ca²⁺ leak function activity and Ca²⁺ overload in the ER. These results provided potential explanation for abnormal Ca²⁺ signaling observed in FAD cells with mutations in presenilns. Our latest work on studies of ER Ca²⁺ leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.     

A Highlights from MBoC Selection: Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons

Disruption of fast axonal transport (FAT) and intracellular Ca²⁺ dysregulation are early pathological events in Alzheimer''s disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca²⁺-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal AβO binding sites are unknown. Here we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca²⁺ elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of AβOs despite compelling reports of presynaptic AβOs in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca²⁺ influx through axonal voltage-gated Ca²⁺ channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca²⁺ release from the ER. This work establishes a novel role for Ca²⁺ dysregulation in BDNF transport disruption and tau-independent Aβ toxicity in early AD.     

Progress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?

After three decades of false hopes and failures, a pipeline of therapeutic drugs that target the actual root cause of Alzheimer's disease (AD) is now available. Challenging the old paradigm that focused on β‐amyloid peptide (Aβ) aggregation in amyloid plaques, these compounds are designed to prevent the neurotoxicity of Aβ oligomers that form Ca²⁺ permeable pores in the membranes of brain cells. By triggering an intracellular Ca²⁺ overdose, Aβ oligomers induce a cascade of neurotoxic events including oxidative stress, tau hyperphosphorylation, and neuronal loss. Targeting any post‐Ca²⁺ entry steps (e.g., tau) will not address the root cause of the disease. Thus, preventing Aβ oligomers formation and/or blocking their toxicity is by essence the best approach to stop any progression of AD. Three categories of anti‐oligomer compounds are already available: antibodies, synthetic peptides, and small drugs. Independent in silico‐based designs of a peptide (AmyP53) and a monoclonal antibody (PMN310) converged to identify a histidine motif (H13/H14) that is critical for oligomer neutralization. This “histidine trick” can be viewed as the Achilles' heel of Aβ in the fight against AD. Moreover, lipid rafts and especially gangliosides play a critical role in the formation and toxicity of Aβ oligomers. Recognizing AD as a membrane disorder and gangliosides as the key anti‐oligomer targets will provide innovative opportunities to find an efficient cure. A “full efficient” solution would also need to be affordable to anyone, as the number of patients has been following an exponential increase, affecting every part of the globe.     

A deuterohemin peptide protects a transgenic Caenorhabditis elegans model of Alzheimer’s disease by inhibiting Aβ1–42 aggregation

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disease and is the most common cause of dementia in the elderly. The main hallmark of AD is the deposition of insoluble amyloid (Aβ) outside the neuron, leading to amyloid plaques and neurofibrillary tangles in the brain. Deuterohemin-Ala-His-Thr-Val-Glu-Lys (DhHP-6), a novel porphyrin-peptide, has both microperoxidase activity and cell permeability. In the present study, DhHP-6 efficiently inhibited the aggregation of Aβ and reduced the β-sheet percentage of Aβ from 89.1% to 78.3%. DhHP-6 has a stronger affinity (K_D = 100 ± 12 μM) for binding with Aβ at Phe⁴, Arg⁵, Val¹⁸, Glu¹¹ and Glu²². In addition, DhHP-6 (100 μM) significantly prolonged lifespan, alleviated paralysis and reduced Aβ plaque formation in the Aβ_1–42 transgenic Caenorhabditis elegans CL4176 model of AD. Our results demonstrate that DhHP-6 is a potential drug candidate that efficiently protects a transgenic C. elegans model of Alzheimer’s disease by inhibiting Aβ aggregation.     

Tau localises within mitochondrial sub-compartments and its caspase cleavage affects ER-mitochondria interactions and cellular Ca2+ handling

Intracellular neurofibrillary tangles (NFT) composed by tau and extracellular amyloid beta (Aβ) plaques accumulate in Alzheimer's disease (AD) and contribute to neuronal dysfunction. Mitochondrial dysfunction and neurodegeneration are increasingly considered two faces of the same coin and an early pathological event in AD. Compelling evidence indicates that tau and mitochondria are closely linked and suggests that tau-dependent modulation of mitochondrial functions might be a trigger for the neurodegeneration process; however, whether this occurs either directly or indirectly is not clear. Furthermore, whether tau influences cellular Ca²⁺ handling and ER-mitochondria cross-talk is yet to be explored. Here, by focusing on wt tau, either full-length (2N4R) or the caspase 3-cleaved form truncated at the C-terminus (2N4RΔC₂₀), we examined the above-mentioned aspects. Using new genetically encoded split-GFP-based tools and organelle-targeted aequorin probes, we assessed: i) tau distribution within the mitochondrial sub-compartments; ii) the effect of tau on the short- (8–10?nm) and the long- (40–50?nm) range ER-mitochondria interactions; and iii) the effect of tau on cytosolic, ER and mitochondrial Ca²⁺ homeostasis. Our results indicate that a fraction of tau is found at the outer mitochondrial membrane (OMM) and within the inner mitochondrial space (IMS), suggesting a potential tau-dependent regulation of mitochondrial functions. The ER Ca²⁺ content and the short-range ER-mitochondria interactions were selectively affected by the expression of the caspase 3-cleaved 2N4RΔC₂₀ tau, indicating that Ca²⁺ mis-handling and defects in the ER-mitochondria communications might be an important pathological event in tau-related dysfunction and thereby contributing to neurodegeneration. Finally, our data provide new insights into the molecular mechanisms underlying tauopathies.     

Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice

Alzheimer's disease (AD) is a neurodegenerative disease displaying extracellular plaques formed by the neurotoxic amyloid β‐peptide (Aβ), and intracellular neurofibrillary tangles consisting of protein tau. However, how these pathologies relate to the massive neuronal death that occurs in AD brains remain elusive. Neprilysin is the major Aβ‐degrading enzyme and a lack thereof increases Aβ levels in the brain twofold. To identify altered protein expression levels induced by increased Aβ levels, we performed a proteomic analysis of the brain of the AD mouse model APPsw and compared it to that of APPsw mice lacking neprilysin. To this end we established an LC‐MS/MS method to analyze brain homogenate, using an ¹⁸O‐labeled internal standard to accurately quantify the protein levels. To distinguish between alterations in protein levels caused by increased Aβ levels and those induced by neprilysin deficiency independently of Aβ, the brain proteome of neprilysin deficient APPsw mice was also compared to that of neprilysin deficient mice. By this approach we identified approximately 600 proteins and the levels of 300 of these were quantified. Pathway analysis showed that many of the proteins with altered expression were involved in neurological disorders, and that tau, presenilin and APP were key regulators in the identified networks. The data have been deposited to the ProteomeXchange Consortium with identifiers PXD000968 and PXD001786 ( http://proteomecentral.proteomexchange.org/dataset/PXD000968 and ( http://proteomecentral.proteomexchange.org/dataset/PXD001786 ). Interestingly, the levels of several proteins, including some not previously reported to be linked to AD, were associated with increased Aβ levels.     

The Na+/Ca2+exchanger in Alzheimer’s disease

As a pivotal player in regulating sodium (Na⁺) and calcium (Ca²⁺) homeostasis and signalling in excitable cells, the Na⁺/Ca²⁺ exchanger (NCX) is involved in many neurodegenerative disorders in which an imbalance of intracellular Ca²⁺ and/or Na⁺ concentrations occurs, including Alzheimer’s disease (AD). Although NCX has been mainly implicated in neuroprotective mechanisms counteracting Ca²⁺ dysregulation, several studies highlighted its role in the neuronal responses to intracellular Na⁺ elevation occurring in several pathophysiological conditions. Since the alteration of Na⁺ and Ca²⁺ homeostasis significantly contributes to synaptic dysfunction and neuronal loss in AD, it is of crucial importance to analyze the contribution of NCX isoforms in the homeostatic responses at neuronal and synaptic levels. Some studies found that an increase of NCX activity in brains of AD patients was correlated with neuronal survival, while other research groups found that protein levels of two NCX subtypes, NCX2 and NCX3, were modulated in parietal cortex of late stage AD brains. In particular, NCX2 positive synaptic terminals were increased in AD cohort while the number of NCX3 positive terminals were reduced. In addition, NCX1, NCX2 and NCX3 isoforms were up-regulated in those synaptic terminals accumulating amyloid-beta (Aβ), the neurotoxic peptide responsible for AD neurodegeneration. More recently, the hyperfunction of a specific NCX subtype, NCX3, has been shown to delay endoplasmic reticulum stress and apoptotic neuronal death in hippocampal neurons exposed to Aβ insult. Despite some issues about the functional role of NCX in synaptic failure and neuronal loss require further studies, these findings highlight the putative neuroprotective role of NCX in AD and open new strategies to develop new druggable targets for AD therapy.     

Impaired TNF-α control of IP3R-mediated Ca2+ release in Alzheimer's disease mouse neurons

The misguided control of inflammatory signaling has been previously implicated in the pathogenesis of several neurological disorders, including Alzheimer's disease (AD). Induction of tumor necrosis factor-alpha (TNF-α), a central mediator of neuroinflammation, occurs commensurate with the onset of early disease in 3xTg-AD mice, which develop both amyloid plaque and neurofibrillary tangle pathologies in an age- and region-dependent pattern. Herein, we describe regulation inherent to 3xTg-AD neurons, which results in the loss of TNF-α mediated enhancement of inositol 1,4,5 trisphosphate (IP₃R)-mediated Ca²⁺ release. This modulation also leads to significant down-regulation of IP₃R signaling following protracted cytokine exposure. Through the experimental isolation of each AD-related transgene, it was determined that expression of the PS1^M146V transgene product is responsible for the loss of the TNF-α effect on IP₃R-mediated Ca²⁺ release. Furthermore, it was determined that the suppression of TNF-α receptor expression occurred in the presence of the presenilin transgene. Our findings attribute this familial AD mutation to suppressing a Ca²⁺-regulated signal cascade potentially intended to “inform” neurons of proximal neuroinflammatory events and trigger compensatory responses for protection of neural transmission.