Tau Protein Dysfunction after Brain Ischemia
Abstract
Brain ischemia comprises blood-brain barrier, glial, and neuronal cells. The blood–brain barrier controls permeability of different substances and the composition of the neuronal cells ‘milieu’, which is required for their physiological functioning. Recent evidence indicates that brain ischemia itself and ischemic blood-brain barrier dysfunction is associated with the accumulation of neurotoxic molecules within brain tissue, e.g., different parts of amyloid-β protein precursor and changed pathologically tau protein. All these changes due to ischemia can initiate and progress neurodegeneration of the Alzheimer’s disease-type. This review presents brain ischemia and ischemic blood-brain barrier as a trigger for tau protein alterations. Thus, we hypothesize that the changes in pattern of phosphorylation of tau protein are critical to microtubule function especially in neurons, and contribute to the neurodegeneration following brain ischemia-reperfusion episodes with Alzheimer’s disease phenotype.
INTRODUCTION
Ischemic stroke in humans is the second cause of death and the third cause of disability, and may soon become the leading cause of death worldwide [1, 2] and dementia of the Alzheimer’s disease (AD) phenotype [3–11]. Acute brain ischemia in patients refers to focal brain infarction that causes sudden neurological deficits and accounts for approximately 87% of all strokes [2]. The latest epidemiological data indicate that about 17 million people suffer from ischemic stroke every year [1, 8]. The number of survivors of ischemic stroke has doubled in 1990-2010 and has now reached 33 million patients [1, 8]. According to epidemiological forecasts, this figure will increase to 77 million by 2030 [1]. Furthermore, stroke survivors are at an increased risk of developing cognitive impairment. Physical impairments following ischemic stroke tend to improve to a greater or lesser degree. However, for reasons unknown, the impairment of cognitive functions is gradually deteriorating. Every year, about 6 million stroke subjects die all over the world [1]. An effective treatment of ischemic stroke involves the use of thrombolysis, but thrombolysis has a limited window of therapeutic time and a potential risk of symptomatic hemorrhagic conversion [2]. Now ischemic stroke exerts a large burden on global public healthcare and clinical practice.
Brain ischemia reduces the supply of oxygen, energy substrates, and nutrients to the brain tissue. In addition, such defects impair the removal of neurotoxic substances, such as the amyloid-β (Aβ) peptide, which accumulates in non-neuronal brain cells, neurons, and extracellular space in animals and humans [12–19]. Recent evidence suggests that ischemia leads to acute and chronic neuronal dysfunction and death, and may contribute to the deposition of various types of neurotoxic proteins, such as various parts of the amyloid-β protein precursor (AβPP), the Aβ peptide, and dysfunctional tau protein, in brain neurons and cerebrovascular system [17, 20, 21]. Such changes include brain amyloidosis and cerebral amyloid angiopathy, which are caused by the progressive accumulation of the Aβ peptide in the brain tissue and vessel wall, respectively, and are recognized as features of AD [17, 22, 23]. It has been suggested that the history of ischemic stroke in humans and experimental brain ischemia are associated with the subsequent development of AD [4, 12, 17, 20, 21, 24–42]. An insidious consistency of post-ischemic brain changes is a slow and progressive development of post-ischemic dementia with AD phenotype [3, 5–11, 43–52]. Patients with AD, who had ischemic injuries, were found to have more intense dementia [53]. Pre-existing ischemic brain damage can further increase the likelihood of AD development by increasing the extent of injury by triggering the genomic and proteomic cascade of AD [20, 32–42]. Thus, the knowledge of the underlying progressive neuropathological mechanisms in the consequences of brain ischemia is urgently required. In this review, we discuss ischemic pathways to the neurodegeneration of the AD phenotype, focusing on the expression of the tau protein gene and its dysfunctional product. This is due to the fact that there is a lot of new information in the literature on genomic and proteomic changes in the tau protein after brain ischemia-reperfusion injury. Presentation of increased expression of the tau protein gene after brain ischemia sheds new light on a better understanding of dysfunctional tau protein as the cause of the effects of ischemic disease [42]. Although significant advances have recently been made in studies on the pathogenicity of tau protein following ischemia, the underlying mechanisms of tau protein-induced post-ischemic neurodegeneration are unclear. Below is an overview of the association of tau protein with post-ischemic neurodegenerative processes. The present review aims at updating knowledge about the connection between brain ischemia and development of AD neuropathology. Therefore, understanding the neuronal mechanisms associated with ischemic brain damage and identifying potential new pathological processes after ischemic stroke is critical to effective therapy for the consequences of stroke. Such studies can help determine the requirements for the implementation of new therapies for ischemic stroke and may be of importance in the conduct and assessment of future prevention priorities.
PROPERTIES OF TAU PROTEIN
Tau protein, a microtubule-associated protein, is present mainly in neurons and at lower levels in oligodendrocytes and astrocytes. Tau protein is coded by a gene on chromosome 17. There are six major isoforms of tau protein in the human brain. Tau protein combines microtubules together and helps stabilize their structure. Microtubules are involved in maintaining the morphology of neurons and creating axonal and dendritic processes, and play an important role in vesicular transport, polarity, and signal transduction. Tau protein may regulate axonal transport by binding to the microtubule surface. Recent reports have revealed several novel functions of tau protein, such as regulation of neuronal activity, maintenance of the integrity of genomic DNA, neurogenesis, iron export, and long-term depression [54, 55]. Understanding the additional functions of tau protein is not only essential to elucidate the tau protein pathogenesis, but it is also necessary to ascertain tau protein-based treatment strategy. Tau protein is natively unfolded with a low content of secondary structure and is divided into an N-terminal domain, a proline-rich region, a repeatable domain, and a C-terminal domain. Tau protein contains a large amount of serine and threonine residues (>80), which are potential phosphorylation sites, and the phosphorylation state, which is controlled by the balance of kinase and phosphatase activity, affects the affinity of microtubule binding. Therefore, the physiological action of tau protein seems to favor the formation of microtubules and stabilize microtubule networks with phosphorylation regulating these functions. In pathological conditions, the tau protein undergoes hyperphosphorylation, and the tau protein binding balance with the microtubule surface is disrupted, resulting in a decrease in affinity for the microtubules [54, 55].
CHANGES IN GENE EXPRESSION OF THE TAU PROTEIN AFTER BRAIN ISCHEMIA-REPERFUSION
Only one existing report in the literature indicates the relationship between the ischemic CA1 region of the hippocampus and the expression of the tau protein gene after transient 10-minute global brain ischemia in rats with a survival of 2, 7, and 30 days [42]. In the hippocampal region of CA1, the expression of the tau protein gene increased to a maximum of 3.3-fold change on the second day after brain ischemia [42]. After 7 days from ischemic episode, the expression was between 0.2 and -0.5-fold change [42]. On the 30th day of survival after ischemic damage to the brain, the expression of the tau protein gene decreased to -0.4-fold [42]. Statistical significance of changes in gene expression of the tau protein following global brain ischemia in rats was between 2 and 7, and between 2 and 30 days of survival [42].
TAU PROTEIN STAINING AFTER BRAIN ISCHEMIA-REPERFUSION
In recent years, several researchers have noted that brain ischemia is an important feature in the development of AD and plays a key role in genomic and proteomic (e.g., AβPP, amyloid processing secretases, autophagy, mitophagy, caspase 3, and tau protein) changes of the disease [20, 32–42, 56, 57]. Early studies revealed that the immunoreactivity of tau protein in neuronal and glial cells had been observed in the thalamus, hippocampus, and cortex in both experimental brain ischemia [58–63] and ischemic stroke in humans [64–66]. Modified tau protein was furthermore noted in microglial cells at the ischemic penumbra [65, 67, 68]. The above data indicate that some neuronal cells display alterations in tau protein following brain ischemia-reperfusion injury [60], which may show a prime neuropathological stage of the ischemic processes in these cells [62]. Another investigation showed that tau protein itself could inhibit transport of AβPP in the neuron body at axons and dendrites, leading to AβPP deposition in the neuronal cell body [69].
The level of tau protein was observed in blood samples after global brain ischemia with two peaks after days 2 and 4, probably indicating the progression of neuronal changes after recirculation [70]. Observed bimodal elevation kinetics of tau protein level in plasma is consistent with two types of neuronal loss: firstly, by necrosis and next via delayed neuronal death [71]. It seems likely that the profiles reflect a time course of primary and secondary ischemic neuronal injury [71]. The above studies suggest that tau protein level in plasma has the potential to be used as a predictor for the neurological outcome following ischemia-reperfusion brain injury [70, 71].
PATTERNS OF TAU PROTEIN PHOSPHORYLATION AFTER BRAIN ISCHEMIA-REPERFUSION
Studies have also shown that the phosphorylation patterns of tau protein differ in different models of brain ischemia (Table 1). Tau protein was dephosphorylated following brain ischemia in several experimental brain ischemia studies (Table 1) [60, 61, 72, 73]. After global brain ischemia and recirculation, tau protein was slowly re-phosphorylated and accumulated (Table 1) [73]. Transient focal brain ischemia with one-day reperfusion induces locally-specific hyperphosphorylation of rat tau protein [74]. In delayed neuronal death in the CA1 region of the hippocampus after transient forebrain ischemia, hyperphosphorylation at serine 199/202 of tau protein is regulated by MAP kinase, CDK5, and GSK3 activities [75]. Also, it was documented that microglia tau protein undergoes phosphorylation-independent modification after brain ischemia in humans (Table 1) [65]. The current investigations indicate that after ischemia, hyperphosphorylated tau protein dominates in cortical neuronal cells and accompanies apoptosis [67, 68, 74, 76–78]. The above-mentioned results indicate that following brain ischemia neuronal apoptosis is straightway associated with tau protein hyperphosphorylation. Wen et al. [74, 76, 77] provided evidence that reversible ischemic brain injury was engaged in neurofibrillary tangle-like development at the rat focal brain ischemia.
Table 1
Various patterns of tau protein dysfunction after brain ischemia-reperfusion
| Tau protein state | Ischemia | Animal/Human | References |
| Neurofibrillary tangle formation | Ischemic stroke | Human | [83] |
| Dephosphorylation | Complete brain ischemia | Rat | [61, 101] |
| Dephosphorylation | Focal brain ischemia | Rat | [60] |
| Rapid dephosphorylation, differential re-phosphorylation | Global brain ischemia | Dog | [73] |
| Microglia tau protein passes independent of phosphorylation modification | Ischemic stroke | Human | [65] |
| Four site-specific hyperphosphorylation at serine 202/214/422 and threonine 231 | Focal brain ischemia | Rat | [74] |
| Hyperphosphorylation at serine 202 and threonine 205 | Global brain ischemia | Rat | [79] |
| Hyperphosphorylation integrated with apoptosis | Focal brain ischemia | Rat | [76] |
| Hyperphosphorylation at serine 199/202 | Forebrain ischemia | Gerbil | [75] |
| Dephosphorylation, rapid re-phosphorylation and hyperphosphorylation | Forebrain ischemia | Gerbil | [102] |
| Neurofibrillary tangle-like tauopathy involving Cdk5 | Focal brain ischemia | Rat | [77] |
| Dephosphorylation associated with adenosine monophosphate kinase (AMPK) dephosphorylation | Global brain ischemia | Rat | [78] |
| Dephosphorylation and hyperphosphorylation at serine 396 | Global brain ischemia | Rat | [67] |
| Hyperphosphorylation and cleavage isoforms of 4- and 3-repeat | Focal brain ischemia | Rat | [68] |
| Reduction tau protein-dependent excitotoxicity in tau–/–mice | Focal brain ischemia | Mouse | [82] |
| Functional damage of tau protein contributes to iron-mediated neurotoxicity | Focal brain ischemia | Mouse/Rat | [80] |
| Hyperphosphorylation involving asparagine endopeptidase | Focal brain ischemia | Mouse | [84] |
| Paired helical filament tau protein increase | Forebrain ischemia | Mouse | [85] |
In addition, the combination of global brain ischemia with hyperhomocysteinemia in rats leads to massive neuronal pathology in the hippocampus and cortex [79]. In the above experimental conditions, 695-fold higher number of hyperphosphorylated tau protein-positive neurons in the cerebral cortex was found compared to the control conditions [79]. Finally, tau protein, a core hallmark of AD, exacerbates brain parenchyma injury in experimental brain ischemia models through tau protein-mediated iron export [80] and tau protein-dependent excitotoxicity [81, 82]. The above results provide a pathological basis for the progress of dementia after brain ischemia-reperfusion with AD phenotype [74, 76, 77].
DYSFUNCTION OF THE BLOOD-BRAIN BARRIER AND TAU PROTEIN AFTER BRAIN ISCHEMIA
Tau protein hyperphosphorylation following brain ischemia-reperfusion episode [67, 68, 74, 76–80, 82–85] induces neurofibrillary tangle-like tauopathy and neurofibrillary tangles [77, 83], which are known to occur in the brains of patients with AD. Brain ischemia causes blood-brain barrier (BBB) permeability [86–90], which may induce hyperphosphorylation of the tau protein [67, 68, 74, 76–80, 82–85, 91], and tau protein dysfunction may cause changes in the BBB, leading to detrimental feedback [92]. Amyloid pathology associated with ischemic BBB dysfunction [93, 94] may indirectly facilitate the onset of tau protein pathology, representing the automatic link between amyloid and tau protein accumulation during BBB failure [92]. Also, both neuroinflammation [95] and oxidative stress [96] induced by BBB insufficiency can trigger tau protein hyperphosphorylation and neurofibrillary tangles formation after brain ischemia [77, 83, 91, 97]. Additionally, blood-borne tau protein after ischemic brain episode [70, 71] can cross the ischemic BBB bi-directionally, and, derived from blood, tau protein may strengthen in brain tissue tau protein pathology [98]. In summary, the BBB insufficiency may potentiate the pathology of the brain tau protein in ischemic brain, and also suggest that brain ischemic neuropathology may contribute to blood tau protein level [70, 71, 98, 99].
DISCUSSION AND CONCLUSIONS
Brain ischemia and AD pathologies often co-exist in brain [22, 23, 53, 100]. In recent years, epidemiological, clinical, and experimental studies have revealed that cerebrovascular diseases including brain ischemia and their history can be proposed as one of the causal factor for AD development. How one condition predisposes to, interacts with, or perhaps causes the others remains unclear. The mechanism of how ischemic stroke could lead to the progression of AD remains obscure. Remarkably, similar etiopathological features can be found in brain ischemic diseases and AD like amyloid and tau protein changes (Table 1). Brain ischemia induces ischemic generation of amyloid plaques that can interact with vascular changes in the brain and progress to AD. Brain ischemia and post-ischemic amyloid accumulation may induce neurodegeneration of the AD phenotype. Generation and deposition of Aβ peptide and tau protein pathology are recognized in post-ischemic forms of neurodegeneration and are important key players in the etiology of the onset and progression of AD. To better understand the link between brain ischemia and AD, we focus in this review on tau protein gene expression and its product post-ischemia.
Tau protein is a phospho-protein and its biological activity is regulated by the degree of its phosphorylation. As tau protein is phosphorylated by kinases involved in different transduction signal pathways, its phosphorylation state is proposed to regulate its binding to microtubules, influencing the dynamics of microtubule assembly necessary for axonal growth and neurite plasticity [101]. Hyperphosphorylated tau protein does not bind or stabilize microtubules, whereas the fully dephosphorylated tau protein binds to microtubules with high affinity. Ischemic brain episode damages the neuronal cytoskeleton both by promoting the proteolysis of its components as well as by affecting the activity of kinases and phosphatases [72, 77]. The state of changes in the phosphorylation of tau protein in various models of brain ischemia and various periods after ischemia are presented in Table 1. Changes in phosphorylation of tau protein may alter its distribution between the axon and the cell body, and affect the susceptibility to proteolysis, affect the stability of microtubules, and may contribute to disruption of axonal transport, but also facilitate the plasticity of neurites in the regenerative response [101]. Hyperphosphorylation of tau protein may contribute to brain damage caused by transient ischemia and recirculation and may be involved in neurodegeneration after brain ischemia [67, 68, 74, 76–80, 82–85]. Thus, changes in phosphorylation of tau protein may play a key role in the process of post-ischemic brain damage.
The relationship between AD-associated tau protein and brain ischemia and ischemic stroke appears quite clear. The worldwide problem and enormous costs involved make it clear that there is an urgent need for advances in the prevention and/or treatment of brain ischemia-reperfusion injury and its irreversible consequences like post-ischemic dementia of AD phenotype. Tau protein plays a key role in neuronal damage and clinical pathophysiology of ischemic stroke. Although the role of ischemia in phosphorylation of tau protein is generally complex and requires further explanation, and the tau protein represents a relatively under-investigated factor in ischemic stroke, we have reason to believe that determining the role of tau protein in ischemic stroke may contribute to understanding the basis for developing a new target for the treatment of ischemic stroke. Finally, regulation of phosphorylation of tau protein can be considered as a potential new therapeutic target after ischemic stroke.
ACKNOWLEDGMENTS
The authors acknowledge support by the Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland (T3-RP) and by the statutory grants from the Medical University of Lublin, Poland (DS 475-SJC).
Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/JAD180772).
REFERENCES
[1] | Bejot Y , Daubail B , Giroud M ((2016) ) Epidemiology of stroke and transient ischemic attacks: Current knowledge and perspectives. Rev Neurol 172: , 59–68. |
[2] | Cassella CR , Jagoda A ((2017) ) Ischemic stroke: Advances in diagnosis and management. Emerg Med Clin N Am 35: , 911–930. |
[3] | Desmond DW , Moroney JT , Sano M , Stern Y ((2002) ) Incidence of dementia after ischemic stroke: Results of a longitudinal study. Stroke 33: , 2254–2260. |
[4] | Honig LS , Tang MX , Albert S , Costa R , Luchsinger J , Manly J , Stern Y , Mayeux R ((2003) ) Stroke and the risk of Alzheimer disease. Arch Neurol 60: , 1707–1712. |
[5] | Jellinger KA ((2007) ) The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathol 113: , 349–388. |
[6] | Pinkston JB , Alekseeva N , Gonzalez Toledo E ((2009) ) Stroke and dementia. Neurol Res 31: , 824–831. |
[7] | Gemmell E , Bosomworth H , Allan L , Hall R , Khundakar A , Oakley AE , Deramecourt V , Polvikoski TM , O’Brien JT , Kalaria RN ((2012) ) Hippocampal neuronal atrophy and cognitive function in delayed poststroke and aging-related dementias. Stroke 43: , 808–814. |
[8] | Brainin M , Tuomilehto J , Heiss WD , Bornstein NM , Bath PM , Teuschl Y , Richard E , Guekht A , Quinn T Post Stroke Cognition Study Group ((2015) ) Post-stroke cognitive decline: An update and perspectives for clinical research. Eur J Neurol 22: , 229–238. |
[9] | Mok VCT , Lam BYK , Wang Z , Liu W , Au L , Leung EYL , Chen S , Yang J , Chu WCW , Lau AYL , Chan AYY , Shi L , Fan F , Ma SH , Ip V , Soo YOY , Leung TWH , Kwok TCY , Ho CL , Wong LKS , Wong A ((2016) ) Delayed-onset dementia after stroke or transient ischemic attack. Alzheimers Dement 12: , 1167–1176. |
[10] | Portegies ML , Wolters FJ , Hofman A , Ikram MK , Koudstaal PJ , Ikram MA ((2016) ) Prestroke vascular pathology and the risk of recurrent stroke and poststroke dementia. Stroke 47: , 2119–2122. |
[11] | Kim JH , Lee Y ((2018) ) Dementia and death after stroke in older adults during a 10-year follow-up: Results from a competing risk model. J Nutr Health Aging 22: , 297–301. |
[12] | Pluta R , Kida E , Lossinsky AS , Golabek AA , Mossakowski MJ , Wisniewski HM ((1994) ) Complete cerebral ischemia with short-term survival in rats induced by cardiac arrest. I. Extracellular accumulation of Alzheimer’s beta-amyloid protein precursor in the brain. Brain Res 649: , 323–328. |
[13] | Jendroska K , Poewe W , Daniel SE , Pluess J , Iwerssen-Schmidt H , Paulsen J , Barthel S , Schelosky L , Cervos-Navarro J , DeArmond SJ ((1995) ) Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol 90: , 461–466. |
[14] | Jendroska K , Hoffmann OM , Patt S ((1997) ) Amyloid β peptide and precursor protein (APP) in mild and severe brain ischemia. Ann NY Acad Sci 826: , 401–405. |
[15] | Wiśniewski HM , Maślińska D ((1996) ) Beta-protein immunoreactivity in the human brain after cardiac arrest. Folia Neuropathol 34: , 65–71. |
[16] | Pluta R ((2000) ) The role of apolipoprotein E in the deposition of β-amyloid peptide during ischemia-reperfusion brain injury. A model of early Alzheimer’s disease. Ann NY Acad Sci 903: , 324–334. |
[17] | Pluta R , Ułamek M , Jabłoński M ((2009) ) Alzheimer’s mechanisms in ischemic brain degeneration. Anat Rec 292: , 1863–1881. |
[18] | Qi J , Wu H , Yang Y , Wand D , Chen Y , Gu Y , Liu T ((2007) ) Cerebral ischemia and Alzheimer’s disease: The expression of amyloid-β and apolipoprotein E in human hippocampus. J Alzheimers Dis 12: , 335–341. |
[19] | Maślińska D , Laure-Kamionowska M , Taraszewska A , Deręgowski K , Maśliński S ((2011) ) Immunodistribution of amyloid beta protein (Aβ) and advanced glycation end-product receptors (RAGE) in choroid plexus and ependyma of resuscitated patients. Folia Neuropathol 49: , 295–300. |
[20] | Pluta R , Furmaga-Jabłońska W , Maciejewski R , Ułamek-Kozioł M , Jabłoński M ((2013) ) Brain ischemia activates β- and γ- secretase cleavage of amyloid precursor protein: Significance in sporadic Alzheimer’s disease. Mol Neurobiol 47: , 425–434. |
[21] | Pluta R , Jabłoński M , Ułamek-Kozioł M , Kocki J , Brzozowska J , Januszewski S , Furmaga-Jabłońska W , Bogucka-Kocka A , Maciejewski R , Czuczwar SJ ((2013) ) Sporadic Alzheimer’s disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer’s disease genes. Mol Neurobiol 48: , 500–515. |
[22] | Kalaria RN ((2000) ) The role of cerebral ischemia in Alzheimer’s disease. Neurobiol Aging 21: , 321–330. |
[23] | Kalaria RN ((2002) ) Small vessel disease and Alzheimer’s dementia: Pathological considerations. Crebrovasc Dis 13: (Suppl 2), 48–52. |
[24] | Pluta R ((1997) ) Experimental model of neuropathological changes characteristic for Alzheimer’s disease. Folia Neuropathol 35: , 94–98. |
[25] | Pluta R ((2006) ) Is the ischemic blood-brain barrier insufficiency responsible for full-blown Alzheimer’s disease? Neurol Res 28: , 266–271. |
[26] | Pluta R , Ułamek M ((2006) ) Brain amyloidosis following ischemia-reperfusion injury. Curr Trends Neurol 2: , 41–46. |
[27] | Pluta R ((2007) ) Role of ischemic blood-brain barrier on amyloid plaques development in Alzheimer’s disease brain. Curr Neurovasc Res 4: , 121–129. |
[28] | Pluta R ((2007) ) Ischemia-reperfusion pathways in Alzheimer’s disease. Nova Science Publishers, Inc., New York. |
[29] | Pluta R , Ułamek M ((2008) ) Brain ischemia and ischemic blood-brain barrier as etiological factors in sporadic Alzheimer’s disease. Neuropsychiatr Dis Treat 4: , 855–864. |
[30] | Pluta R , Januszewski S , Jabłoński M , Ułamek M ((2010) ) Factors in creepy delayed neuronal death in hippocampus following brain ischemia–reperfusion injury with long-term survival. Acta Neurochir 106: (Suppl), 37–41. |
[31] | Pluta R , Ułamek M , Jabłoński M ((2010) ) Consideration of the ischaemic basis and treatment of Alzheimer’s disease. Folia Neuropathol 48: , 11–26. |
[32] | Kocki J , Ułamek-Kozioł M , Bogucka-Kocka A , Januszewski S , Jabłoński M , Gil-Kulik P , Brzozowska J , Petniak A , Furmaga-Jabłońska W , Bogucki J , Czuczwar SJ , Pluta R ((2015) ) Dysregulation of amyloid precursor protein, β-secretase, presenilin 1 and 2 genes in the rat selectively vulnerable CA1 subfield of hippocampus following transient global brain ischemia. J Alzheimers Dis 47: , 1047–1056. |
[33] | Pluta R , Kocki J , Ułamek-Kozioł M , Bogucka-Kocka A , Gil-Kulik P , Januszewski S , Jabłoński M , Petniak A , Brzozowska J , Bogucki J , Furmaga-Jabłońska W , Czuczwar SJ ((2016) ) Alzheimer-associated presenilin 2 gene is dysregulated in rat medial temporal lobe cortex after complete brain ischemia due to cardiac arrest. Pharmacol Rep 68: , 155–161. |
[34] | Pluta R , Kocki J , Ułamek-Kozioł M , Petniak A , Gil-Kulik P , Januszewski S , Bogucki J , Jabłoński M , Brzozowska J , Furmaga-Jabłońska W , Bogucka-Kocka A , Czuczwar SJ ((2016) ) Discrepancy in expression of β-secretase and amyloid-β protein precursor in Alzheimer-related genes in the rat medial temporal lobe cortex following transient global brain ischemia. J Alzheimers Dis 51: , 1023–1031. |
[35] | Ułamek-Kozioł M , Kocki J , Bogucka-Kocka A , Petniak A , Gil-Kulik P , Januszewski S , Bogucki J , Jabłoński M , Furmaga-Jabłońska W , Brzozowska J , Czuczwar SJ , Pluta R ((2016) ) Dysregulation of autophagy, mitophagy and apoptotic genes in the medial temporal lobe cortex in an ischemic model of Alzheimer’s disease. J Alzheimers Dis 54: , 113–121. |
[36] | Ułamek-Kozioł M , Pluta R , Januszewski S , Kocki J , Bogucka-Kocka A , Czuczwar SJ ((2016) ) Expression of Alzheimer’s disease risk genes in ischemic brain degeneration. Pharmacol Rep 68: , 1345–1349. |
[37] | Ułamek-Kozioł M , Pluta R , Bogucka-Kocka A , Januszewski S , Kocki J , Czuczwar SJ ((2016) ) Brain ischemia with Alzheimer phenotype dysregulates Alzheimer’s disease-related proteins. Pharmacol Rep 68: , 582–591. |
[38] | Pluta R , Ułamek-Kozioł M , Januszewski S , Czuczwar SJ ((2017) ) Dysregulation of Alzheimer’s disease-related genes and proteins following cardiac arrest. Folia Neuropathol 55: , 283–288. |
[39] | Salminen A , Kauppinen A , Kaarniranta K ((2017) ) Hypoxia/ischemia activate processing of amyloid precursor protein: Impact of vascular dysfunction in the pathogenesis of Alzheimer’s disease. J Neurochem 140: , 536–549. |
[40] | Ułamek-Kozioł M , Kocki J , Bogucka-Kocka A , Januszewski S , Bogucki J , Czuczwar SJ , Pluta R ((2017) ) Autophagy, mitophagy and apoptotic gene changes in the hippocampal CA1 area in a rat ischemic model of Alzheimer’s disease. Pharmacol Rep 69: , 1289–1294. |
[41] | Pluta R , Ułamek-Kozioł M ((2018) ) Alzheimer’s disease associated genes and their products in brain ischemia: Impact of ischemia on the pathogenesis of Alzheimer’s disease. J Ageing Restor Med 1: , 19–27. |
[42] | Pluta R , Bogucka-Kocka A , Ułamek-Kozioł M , Bogucki J , Kocki J , Czuczwar SJ ((2018) ) Ischemic tau protein gene induction as an additional key factor driving development of Alzheimer’s phenotype changes in CA1 area of hippocampus in an ischemic model of Alzheimer’s disease. Pharmacol Rep 70: , 881–884. |
[43] | Kuroiwa T , Bonnekoh P , Hossmann KA ((1991) ) Locomotor hyperactivity and hippocampal CA1 injury after transient forebrain ischemia in gerbils. Neurosci Lett 122: , 141–144. |
[44] | Karasawa Y , Araki H , Otomo S ((1994) ) Changes in locomotor activity and passive avoidance task performance induced by cerebral ischemia in mongolian gerbils. Stroke 25: , 645–650. |
[45] | Block F ((1999) ) Global ischemia and behavioural deficits. Prog Neurobiol 58: , 279–295. |
[46] | Ishibashi S , Kuroiwa T , LiYuan S , Katsumata N , Li S , Endo S , Mizusawa H ((2006) ) Long-term cognitive and neuropsychological symptoms after global cerebral ischemia in Mongolian gerbils. Acta Neurochir 96: (Suppl), 299–302. |
[47] | Barra de la Tremblaye P , Plamondon H ((2011) ) Impaired conditioned emotional response and object recognition are concomitant to neuronal damage in the amygdale and perirhinal cortex in middle-aged ischemic rats. Behav Brain Res 219: , 227–233. |
[48] | Kiryk A , Pluta R , Figiel I , Mikosz M , Ułamek M , Niewiadomska G , Jabłoński M , Kaczmarek L ((2011) ) Transient brain ischemia due to cardiac arrest causes irreversible long-lasting cognitive injury. Behav Brain Res 219: , 1–7. |
[49] | Li J , Wang YJ , Zhang M , Fang CQ , Zhou HD ((2011) ) Cerebral ischemia aggravates cognitive impairment in a rat model of Alzheimer’s disease. Life Sci 89: , 86–92. |
[50] | Pluta R , Jolkkonen J , Cuzzocrea S , Pedata F , Cechetto D , Popa-Wagner A ((2011) ) Cognitive impairment with vascular impairment and degeneration. Curr Neurovasc Res 8: , 342–350. |
[51] | Cohan CH , Neumann JT , Dave KR , Alekseyenko A , Binkert M , Stransky K , Lin HW , Barnes CA , Wright CB , Perez-Pinzon MA ((2015) ) Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats. PLoS One 10: , e0124918. |
[52] | Zhang T , Liu X , Li Q , Wang J , Jia W , Sun X ((2010) ) Exacerbation of ischemia-induced amyloid-beta generation by diabetes is associated with autophagy activation in mice brain. Neurosci Lett 479: , 215–220. |
[53] | Snowdon DA , Greiner LH , Mortimer JA , Riley KP , Greiner PA , Markesbery WR ((1997) ) Brain infarction and the clinical expression of Alzheimer disease: The Nun Study. JAMA 277: , 813–817. |
[54] | Gao YL , Wang N , Sun FR , Cao XP , Zhang W , Yu JT ((2018) ) Tau in neurodegenerative disease. Ann Transl Med 6: , 175. |
[55] | Goedert M ((2018) ) Tau filaments in neurodegenerative diseases. FEBS Lett 592: , 2383–2391. |
[56] | Pluta R ((2004) ) Alzheimer lesions after ischemia-reperfusion brain injury. Folia Neuropathol 42: , 181–186. |
[57] | Pluta R ((2004) ) From brain ischemia-reperfusion injury to possible sporadic Alzheimer’s disease. Curr Neurovasc Res 1: , 441–453. |
[58] | Dewar D , Graham DI , Teasdale GM , McCulloch J ((1993) ) Alz-50 and ubiquitin immunoreactivity is induced by permanent focal cerebral ischaemia in the cat. Acta Neuropathol 86: , 623–629. |
[59] | Dewar D , Graham DI , Teasdale GM , McCulloch J ((1994) ) Cerebral ischemia induces alterations in tau and ubiquitin proteins. Dementia 5: , 168–173. |
[60] | Dewar D , Dawson D ((1995) ) Tau protein is altered by focal cerebral ischaemia in the rat: An immunohistochemical and immunoblotting study. Brain Res 684: , 70–78. |
[61] | Geddes JW , Schwab C , Craddock S , Wilson JL , Pettigrew LC ((1994) ) Alterations in tau immunostaining in the rat hippocampus following transient cerebral ischemia. J Cereb Blood Flow Metab 14: , 554–564. |
[62] | Irving EA , Yatsushiro K , McCulloch J , Dewar D ((1997) ) Rapid alteration of tau in oligodendrocytes after focal ischemic injury in the rat: Involvement of free radicals. J Cereb Blood Flow Metab 17: , 612–622. |
[63] | Sinigaglia-Coimbra R , Cavalheiro EA , Coimbra CG ((2002) ) Postischemic hypertermia induces Alzheimer-like pathology in the rat brain. Acta Neuropathol 103: , 444–452. |
[64] | Uchihara T , Tsuchiya K , Kondo H , Hayama T , Ikeda K ((1995) ) Widespread appearance of Alz-50 immunoreactive neurons in the human brain with cerebral infarction. Stroke 26: , 2145–2148. |
[65] | Uchihara T , Nakamura A , Arai T , Ikeda K , Tsuchiya K ((2004) ) Microglial tau undergoes phosphorylation-independent modification after ischemia. Glia 45: , 180–187. |
[66] | Irving EA , Nicoll J , Graham DI , Dewar D ((1996) ) Increased tau immunoreactivity in oligodendrocytes following human stroke and head injury. Neurosci Lett 213: , 189–192. |
[67] | Majd S , Power JH , Koblar SA , Grantham HJM ((2016) ) Introducing a developed model of reversible cardiac arrest to produce global brain ischemia and its impact on microtubule-associated protein tau phosphorylation at Ser396. Int J Neurol Neurother 3: , 040. |
[68] | Fujii H , Takahashi T , Mukai T , Tanaka S , Hosomi N , Maruyama H , Sakai N , Matsumoto M ((2017) ) Modifications of tau protein after cerebral ischemia and reperfusion in rats are similar to those occurring in Alzheimer’s disease - Hyperphosphorylation and cleavage of 4- and 3-repeat tau. J Cereb Blood Flow Metab 37: , 2441–2457. |
[69] | Stamer K , Vogel R , Thies E , Mandelkow E , Mandelkow EM ((2002) ) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 156: , 1051–1063. |
[70] | Mörtberg E , Zetterberg H , Nordmark J , Blennow K , Catry C , Decraemer H , Vanmechelen E , Rubertsson S ((2011) ) Plasma tau protein in comatose patients after cardiac arrest treated with therapeutic hypothermia. Acta Anaesthesiol Scand 55: , 1132–1138. |
[71] | Randall J , Mörtberg E , Provuncher GK , Fournier DR , Duffy DC , Rubertsson S , Blennow K , Zetterberg H , Wilson DH ((2013) ) Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: Results of a pilot study. Resuscitation 84: , 351–356. |
[72] | Shackelford DA , Nelson KE ((1996) ) Changes in phosphorylation of tau during ischemia and reperfusion in the rabbit spinal cord. J Neurochem 66: , 286–295. |
[73] | Mailliot C , Podevin-Dimster V , Rosenthal RE , Sergeant N , Delacourte A , Fiskum G , Buée L ((2000) ) Rapid tau protein dephosphorylation and differential rephosphorylation during cardiac arrest-induced cerebral ischemia and reperfusion. J Cereb Blood Flow Metab 20: , 543–549. |
[74] | Wen Y , Yang S , Liu R , Simpkins JW ((2004) ) Transient cerebral ischemia induces site-specific hyperphosphorylation of tau protein. Brain Res 1022: , 30–38. |
[75] | Morioka M , Kawano T , Yano S , Kai Y , Tsuiki H , Yoshinaga Y , Matsumoto J , Maeda T , Hamada J , Yamamoto H , Fukunaga K , Kuratsu J ((2006) ) Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischemia. Biochem Biophys Res Commun 347: , 273–278. |
[76] | Wen Y , Yang S , Liu R , Brun-Zinkernagel AM , Koulen P , Simpkins JW ((2007) ) Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimer’s disease-like tauopathy in female rats. J Biol Chem 279: , 22684–22692. |
[77] | Wen Y , Yang SH , Liu R , Perez EJ , Brun-Ziukemagel AM , Koulen P , Simpkins JW ((2007) ) Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta 1772: , 473–483. |
[78] | Majd S , Power JH , Koblar SA , Grantham HJ ((2016) ) Early glycogen synthase kinase-3β and protein phosphatase 2A independent tau dephosphorylation during global brain ischaemia and reperfusion following cardiac arrest and the role of the adenosine monophosphate kinase pathway. Eur J Neurosci 44: , 1987–1997. |
[79] | Kovalska M , Tothova B , Kovalska L , Tatarkova Z , Kalenska D , Tomascova A , Adamkov M , Lehotsky J ((2018) ) Association of induced hyperhomocysteinemia with Alzheimer’s disease-like neurodegeneration in rat cortical neurons after global ischemia-reperfusion injury. Neurochem Res 43: , 1766–1778. |
[80] | Tuo Q Z , Lei P , Jackman K A , Li XL , Xiong H , Li XL , Liuyang ZY , Roisman L , Zhang ST , Ayton S , Wang Q , Crouch PJ , Ganio K , Wang XC , Pei L , Adlard PA , Lu YM , Cappai R , Wang JZ , Liu R , Bush AI ((2017) ) Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry 22: , 1520–1530. |
[81] | Pluta R , Salínska E , Puka M , Stafiej A , Lazarewicz JW. ((1988) ) Early changes in extracellular amino acids and calcium concentrations in rabbit hippocampus following complete 15-min cerebral ischemia. Resuscitation 16: , 193–210. |
[82] | Bi M , Gladbach A , van Eersel J , Ittner A , Przybyla M , van Hummel A , Chua SW , van der Hoven J , Lee WS , Müller J , Parmar J , Jonquieres GV , Stefen H , Guccione E , Fath T , Housley GD , Klugmann M , Ke YD , Ittner LM ((2017) ) Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nat Commun 8: , 473. |
[83] | Kato T , Hirano A , Katagiri T , Sasaki H , Yamada S ((1988) ) Neurofibrillary tangle formation in the nucleus basalis of Meynert ipsilateral to a massive cerebral infarct. Ann Neurol 23: , 620–623. |
[84] | Basurto-Islas G , Gu JH , Tung YC , Liu F , Iqbal K ((2018) ) Mechanism of tau hyperphosphorylation involving lysosomal enzyme asparagine endopeptidase in a mouse model of brain ischemia. J Alzheimers Dis 63: , 821–833. |
[85] | Khan S , Yuldasheva NY , Batten TFC , Pickles AR , Kellett KAB , Saha S ((2018) ) Tau pathology and neumical changes associated with memory dysfunction in an optimised murine model of global cerebral ischaemia - A potential model for vascular dementia? Neurochem Int 118: , 134–144. |
[86] | Pluta R , Lossinsky AS , Wisniewski HM , Mossakowski MJ ((1994) ) Early blood-brain barrier changes in the rat following transient complete cerebral ischemia induced by cardiac arrest. Brain Res 633: , 41–52. |
[87] | Pluta R ((2003) ) Blood-brain barrier dysfunction and amyloid precursor protein accumulation in microvascular compartment following ischemia-reperfusion brain injury with 1-year survival. Acta Neurochir 86: (Suppl), 117–122. |
[88] | Pluta R ((2005) ) Pathological opening of the blood-brain barrier to horseradish peroxidase and amyloid precursor protein following ischemia-reperfusion brain injury. Chemotherapy 51: , 223–226. |
[89] | Pluta R , Ułamek M , Januszewski S ((2006) ) Micro-blood–brain barrier openings and cytotoxic fragments of amyloid precursor protein accumulation in white matter after ischemic brain injury in long-lived rats. Acta Neurochir 96: (Suppl), 267–271. |
[90] | Pluta R , Januszewski S , Ułamek M ((2008) ) Ischemic blood–brain barrier and amyloid in white matter as etiological factors in leukoaraiosis. Acta Neurochir 102: (Suppl), 353–356. |
[91] | Michalicova A , Banks WA , Legath J , Kovac A ((2017) ) Tauopathies - focus on changes at the neurovascular unit. Curr Alzheimer Res 14: , 790–801. |
[92] | Ramos-Cejudo J , Wisniewski T , Marmar C , Zetterberg H , Blennow K , de Leon MJ , Fossati S ((2018) ) Traumatic brain injury and Alzheimer’s disease: The cerebrovascular link. EBioMedicine 28: , 21–30. |
[93] | Lee PH , Bang OY , Hwang EM , Lee JS , Joo US , Mook-Jung I , Huh K ((2005) ) Circulating beta amyloid protein is elevated in patients with acute ischemic stroke. J Neural Transm 112: , 1371–1379. |
[94] | Zetterberg H , Mörtberg E , Song L , Chang L , Provuncher GK , Patel PP , Ferrell E , Fournier DR , Kan CW , Campbell TG , Meyer R , Rivnak AJ , Pink BA , Minnehan KA , Piech T , Rissin DM , Duffy DC , Rubertsson S , Wilson DH , Blennow K ((2011) ) Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans. PLoS One 6: , e28263. |
[95] | Sekeljic V , Bataveljic D , Stamenkovic S , Ułamek M , Jabłoński M , Radenovic L , Pluta R , Andjus PR ((2012) ) Cellular markers of neuroinflammation and neurogenesis after ischemic brain injury in the long-term survival rat model. Brain Struct Funct 217: , 411–420. |
[96] | Li P , Stetler RA , Leak RK , Shi Y , Li Y , Yu W , Bennett MVL , Chen J ((2018) ) Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology 134: (Pt B), 208–217. |
[97] | Kumfu S , Charununtakorn ST , Jaiwongkam T , Chattipakorn N , Chattipakorn SC ((2018) ) Humanin exerts neuroprotection during cardiac ischemia-reperfusion injury. J Alzheimers Dis 61: , 1343–1353. |
[98] | Banks WA , Kovac A , Majerova P , Bullock KM , Shi M , Zhang J ((2017) ) Tau proteins cross the blood-brain barrier. J Alzheimers Dis 55: , 411–419. |
[99] | Ueno M , Chiba Y , Murakami R , Matsumoto K , Kawauchi M , Fujihara R ((2016) ) Blood-brain barrier and blood-cerebrospinal fluid barrier in normal and pathological conditions. Brain Tumor Pathol 33: , 89–96. |
[100] | Pluta R , Bogucka-Kocka A , Ułamek-Kozioł M , Furmaga-Jabłońska W , Januszewski S , Brzozowska J , Jabłoński M , Kocki J ((2015) ) Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: Is there a role for curcumin? Folia Neuropathol 53: , 89–99. |
[101] | Shackelford DA , Yeh RY ((1998) ) Dephosphorylation of tau during transient forebrain ischemia in the rat. Mol Chem Neuropathol 34: , 103–120. |
[102] | Gordon-Krajcer W , Kozniewska E , Lazarewicz JW , Ksiezak-Reding H ((2007) ) Differential changes in phosphorylation of tau at PHF-1 and 12E8 epitopes during brain ischemia and reperfusion in gerbils. Neurochem Res 32: , 729–737. |
