A cholesterol/glucose dysmetabolism initiated Tau-driven AOP toward memory loss (AO) in sporadic Alzheimer's Disease with plausible MIE's plug-ins for environmental neurotoxicants

• Erwin L Roggen
• Brendan Ferreri-Hanberry

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Homo sapiens

KER4: Mitochondrial dysfunction (KE1) - Oxidative stress (KE2)

The biological plausibility: Pathological ROS levels result in oxidation and loss of function of proteins, lipids, and nucleic acids. The resulting oxidative stress directly, or via mitochondrial dysfunction, results in less mitochondrial biomass, intracellular ATP and respiratory complexes, elevated concentration of intracellular Ca²⁺ and activated Ca²⁺-dependent calpains, cellular dysfunction and eventually cell death [70, 136-138].

The empirical support: Oxidative imbalance is predominant in AD pathogenesis [139, 140]. Accumulated 8-oxoguanine (8-oxoG), oxidized guanine, a marker for nuclear and mitochondrial DNA damage, has been found in postmortem AD hippocampus [141, 142]. Enhanced lipid peroxidation, oxidized protein and nucleic acids, and a significant decrease in antioxidant enzyme activity are reported in AD [131, 136, 143]. Proteomic analysis shows a 2-fold increase in mitochondrial protein nitration and oxidation in subjects with MCI when compared to healthy subjects, but not in AD subjects, suggesting that mitochondrial dysfunction occurs during early development of disease [144]. Several studies report that neuronal stress increases cytosolic Ca²⁺-activated calpain expression leading to neuropathological diseases, such as AD [145-147].

Overall assessment: Data suggest that GSH depletion and mitochondrial dysfunction are plausible causes for excessive ROS levels, but lack quantitative data about threshold, magnitude, and duration. KER4 describes the link between the upstream event ‘mitochondrial dysfunction’ and the downstream event ‘oxidative stress’. Both events are considered adjacent, despite the evidence for this relation is classified as moderate due to some  inconsistencies.

KER5: Oxidative Stress (KE2) - p-tau (KE3)

The biological plausibility: The evidence suggest that ROS induced oxidative stress promotes pathological tau modifications and disruption of the mechanisms involved in proper mitochondrialfunctionality [139, 150-152]. Hyperphosphorylation of tau disrupts its affinity for microtubules, increases its resistance to degradation, and induces conformational changes promoting aggregation [49]. Hence, a proper regulation between tau protein phosphorylation and dephosphorylation of the many phosphorylation sites of tau is detrimental for a healthy neuronal cell physiology [153-155]. Under excessive oxidative stress Ca²⁺-dependent calpains activate cyclin-dependent kinase 5 (Cdk5) and GSK3β, both involved in tau hyperphosphorylation and shown to be important for proper neural development, synaptic signaling, learning and memory [155, 156]. Cdk5 and GSK3β interact with the truncated regulatory unit of p35 (p25), also a product of calpain activation [157]. Cdk5/p25 and GSK3β/p25 mediated tau phosphorylation decreases the affinity of tau for microtubules, disrupts the cytoskeleton and causes apoptosis [158, 159]. The GSK3β/p25 complex inhibits PP2A phosphorylation through increased inhibitory Tyr307 phosphorylation and decreases expression of PP2A [160]. The data suggest a GSK3β-Cdk5-PP2A synergy in tauopathy, which is characterized by decreased affinity of tau for microtubules, abnormal hyperphosphorylation, aggregation and eventually synaptic dysfunction [161-164]. 

The empirical support: Mitochondrial dysfunction (KE1) and/or oxidative stress (KE2) activate the calpain signaling pathway, a process that precedes p-tau formation during the early stages of AD development [165]. Available evidence suggests that oxidative stress through tau hyperphosphorylation contributes to tau pathology and AD [166]. Calpain mediated activation of the tau kinases Cdk5 and GSK3β correlates with the degree of pathology (Braak stage II-III) and precedes tau phosphorylation and synaptic loss [165]. Proteomic analysis suggests that loss of function of neuronal peptidyl prolyl cis-trans isomerase 1 (Pin1) by oxidative damage, and its downregulation in AD hippocampus, are linked to tau phosphorylation and AD neurofibrillary pathology [167]. The observation that human truncated tau protein expression leads to accumulation of ROS and cortical neuron death in rats, suggests that tau modification may also precede oxidative stress [168].

Overall assessment: Data support that excessive ROS levels are a plausible cause for tau pathology, and that both events are adjacent. Even though it technologically is possible to measure ROS levels in vitro, it was not possible to find threshold and magnitude values, nor duration of exposure, that are  required to result in a persistent adverse impact on p-tau levels.

KER7: Dysfunctional autophagy (KE4) - cytosolic toxic tau (KE5)

The biological plausibility: Progressive dysfunction of neuronal autophagic capacity contributes to the formation of an initiating substrate complex needed for the initial seeding (or nucleation) of tau (and Aβ) aggregation. As a result, cytosolic tau oligomers are formed, followed by UPS-mediated autocatalytic propagation of tau aggregation [33]. At synaptic sites, accumulated tau oligomers are correlated with accumulated ubiquitinated proteins, proteasomes and related chaperones [200]. 

The empirical support: Cytosolic toxic tau oligomers are observed at very early stages of the AD [173], with human AD brain containing more tau oligomers than control samples [201]. Inhibition of autophagy in a neuroblastoma cell model of tauopathy results in elevated levels of soluble and insoluble forms of tau [199]. Observations of internalized tau aggregates colocalizing with lysosomal markers suggest a plausible role of autophagy in tau degradation or lack thereof when dysfunctional. Supporting evidence is provided by a study showing that intracellular tau seed-induced aggregate formation is inhibited by activation of autophagy with rapamycin [202]. 

Overall assessment: It is plausible that a decreasing capacity to exhibit effective autophagy (KE4), in an environment of elevated p-tau (KE3), plays an important role in the accumulation of cytosolic pathologic tau variants (KE5). While the data indicate that defective autophagy, elevated p-tau and cytosolic tau levels are adjacent, there were no quantitative data found concerning threshold, magnitude or duration required to observe an adverse effect driving the development of memory loss.

KER8: Cytosolic toxic tau (KE5) - dysfunctional axonal transport (KE6), KER9: dysfunctional axonal transport (KE6) - dysfunctional synapses (KE7), KER10: dysfunctional synapses (KE7) - neuronal dysfunction (KE9)

The biological plausibility: Tau protein drives cognitive impairment by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor pathways [203]. In the neuronal dendrites, p-tau targets Fyn kinase, a substrate for the NMDA receptor at postsynaptic compartments [204, 205]. This results in delocalization of tau from axon to synapses and somatodendritic compartments, which causes NFT formation and eventually synaptic dysfunction [153, 171]. Soluble tau oligomers exert more acute toxicity than the insoluble ones [206]. Especially dimers are effectively self-associating into large oligomeric tau nuclei of aggregation. These pathological tau aggregates are cytosolic, but also appear in the extracellular space, and correlate with synaptic dysfunction, neuronal toxicity, and degeneration [206, 207]. In human induced pluripotent stem cells (iPSC)-derived neurons, induction of tau oligomers, but not monomers, drives pathological p-tau aggregation and causes neurite retraction, synaptic loss, neurotransmitters imbalance and neuronal cell death [202]. In mice, subcortical injection of oligomers reduces the expression of synaptic vesicle-associated proteins leading to synaptic dysfunction. Pathogenic tau oligomers also negatively affect mitochondria, suggesting an amplifying circle of toxic Ca²⁺-mediated events linking KE3 and KE5, and leading to mitochondrial dysfunction and synaptic loss [208, 209]. Tau-induced mitochondrial dysfunction (KE1) is characterized by a decrease in mitochondrial complex I levels, activation of caspase-9 and the apoptotic mitochondrial pathway [208]. Toxic Tau35 may be implicated in intraneuronal insulin accumulation and impaired insulin signaling through interactions with phosphatase and tensin homolog protein (PTEN), which inhibits dephosphorylation of PIP3 to PIP2 [210, 211].

The empirical support: Synaptic loss is associated with early cognitive decline in the neocortex and limbic system, with reductions in synaptic density at preclinical and terminal stage in AD pathology of 25% and 55%, respectively [212, 213]. The levels of markers for presynaptic terminals, synaptic vesicle and synaptic protein are reduced in early stage of AD [214]. Along the same line, a tau transgenic mouse was found to exhibit a decreased expression of synaptic proteins, such as synaptophysin, synapsin, synaptojanin, and synaptobrevin [203]. An acute exposure to extracellular human tau oligomers caused memory impairment in mice [215] probably through inhibition of IRS1 and PTEN activities and subsequent insulin resistance. Abnormal inhibitory serine phosphorylation of IRS1 by INSR has been linked to brain insulin resistance in tauopathy, including AD pathology [211].

Overall assessment: The evidence supports enhanced cytosolic toxic tau levels (KE5) being adjacent to dysfunctional axonal transport (KE6) which results subsequently in synaptic (KE7) and neural (KE9) dysfunction. Thresholds values, degree, and duration of dysfunction of these KEs required to drive this series KEs towards memory loss are not known.

KER11: Toxic tau oligomers (KE5) - Neuroinflammation (KE8), KER12: Neuroinflammation (KE8) - Neuronal dysfunction (KE9)

The biological plausibility: Small soluble tau oligomers cause inflammatory signalling in the brain by activating microglia. These inflammatory responses are mediated by activated inflammasome and promote proinflammatory interleukin 1β (IL-1β) release, which is controlled by activation of caspase-1[217]. Activation of microglia and astroglia, and subsequent release of proinflammatory cytokines occur in the brain of humans and mice exposed to p-tau [218, 219]. Colocalization of activated microglia and astroglia, and proinflammatory cytokines with tau oligomers has been observed in mouse brain, suggesting that tau oligomers play a role in neuroinflammation and in accelerating neuronal dysfunction and neurodegeneration [220]. Tau oligomer levels correlate with High Mobility Group Box 1 (HMGB1) levels, an important pro-inflammatory marker in the brain [220], with recruitment of brain T-cells being linked to tau pathology and neuroinflammatory processes [221, 222].

The empirical support: Neuroinflammatory response in AD brain is driven by potent inflammatory mediators [223] and free radicals [224]. In a cross-sectional study of elderly adults with normal cognition and impaired cognition, six CSF neuroinflammatory markers (interleukin 15 (IL-15), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor receptor 1 (VEGFR-1), soluble intercellular adhesion molecule-1 (sICAM1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and vascular endothelial growth factor-D (VEGF-D)) correlated with tau levels in CSF, while none correlated with Aβ levels in CSF [225]. 

Overall assessment: There is strong evidence that processes resulting in increased cytosolic toxic tau levels (KE5) are adjacent to neuroinflammation (KE8), a condition that is widely accepted to play an important role in memory loss (AO) and neurodegeneration. The levels of cytotoxic tau, nor the duration of exposure, required to obtain a detectable inflammatory response sufficient to drive neuronal dysfunction are not known.

KER13: Neuronal dysfunction (KE9) - Memory loss (AO)

Neuronal dysfunction is one of the most well-characterized hallmarks in AD pathogenesis. Particularly, loss of memory at early stage of the disease is associated with neuronal dysfunction in the upper layer of entorhinal cortex, an early affected brain region in preclinical state of the disease [226]. Synaptic dysfunction results in cognitive impairment and neuronal cell death [202, 227, 228]. Brain insulin signaling impairment decreases AKT signaling, which is crucial for cell survival and function [229] and negatively affects synaptic plasticity and memory [230, 231]. A toxic relationship exists between soluble tau oligomers and neuroinflammation, which cause eventually neuronal damage, activating inflammatory mediators and free radicals [220, 223, 224]. In AD mouse models, chronic neuronal tumor necrosis factor α (TNF-α) expression correlates with neuronal death [232]. Significant loss in neuronal density occurs in the hippocampus and cerebral cortex of AD patients [233-235], and is AD-stage dependent [236].

Overall assessment: Despite the lack of data on quantity and temporality data, the evidence supports neuronal dysfunction (KE9) to be adjacent to memory loss (AO).