Neurodegenerative diseases constitute a group of chronic disorders characterized by the progressive loss of neurons. Major neurodegenerative conditions include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Pathologically, these diseases are marked by the accumulation of aggregates formed by pathological proteins such as amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. These proteins assemble into amyloid fibrils that undergo prion-like propagation and dissemination, ultimately inducing neurodegeneration. Understanding the biology of these protein aggregates is fundamental to elucidating the pathophysiology of neurodegenerative disorders. In this review, we summarize the molecular mechanisms underlying the aggregation and transmission of pathological proteins, the processes through which these protein aggregates trigger neurodegeneration, and the interactions between different pathological proteins. We also provide an overview of the current diagnostic approaches and therapeutic strategies targeting pathological protein aggregates.
Humans ; Neurodegenerative Diseases/metabolism* ; alpha-Synuclein/metabolism* ; Amyloid beta-Peptides/metabolism* ; tau Proteins/metabolism* ; Protein Aggregation, Pathological/metabolism* ; DNA-Binding Proteins/metabolism* ; Animals ; Protein Aggregates/physiology*

Hypoxic-ischemic brain damage (HIBD) is one of the main causes of disability in middle-aged and elderly people, as well as high mortality rates and long-term physical impairments in newborns. The pathological manifestations of HIBD include neuronal damage and loss of myelin sheaths. Tau protein is an important microtubule-associated protein in brain, exists in neurons and oligodendrocytes, and regulates various cellular activities such as cell differentiation and maturation, axonal transport, and maintenance of cellular cytoskeleton structure. Phosphorylation is a common chemical modification of Tau. In physiological condition, it maintains normal cell cytoskeleton and biological functions by regulating Tau structure and function. In pathological conditions, it leads to abnormal Tau phosphorylation and influences its structure and functions, resulting in Tauopathies. Studies have shown that brain hypoxia-ischemia could cause abnormal alteration in Tau phosphorylation, then participating in the pathological process of HIBD. Meanwhile, brain hypoxia-ischemia can induce oxidative stress and inflammation, and multiple Tau protein kinases are activated and involved in Tau abnormal phosphorylation. Therefore, exploring specific molecular mechanisms by which HIBD activates Tau protein kinases, and elucidating their relationship with abnormal Tau phosphorylation are crucial for future researches on HIBD related treatments. This review aims to focus on the mechanisms of the role of Tau phosphorylation in HIBD, and the potential relationships between Tau protein kinases and Tau phosphorylation, providing a basis for intervention and treatment of HIBD.
Humans ; tau Proteins/physiology* ; Phosphorylation ; Hypoxia-Ischemia, Brain/physiopathology* ; Animals ; Oxidative Stress

Alzheimer Disease ; complications ; pathology ; therapy ; Amyloid beta-Peptides ; metabolism ; Humans ; Mitochondria ; physiology ; Mitochondrial Diseases ; etiology ; tau Proteins ; metabolism

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.
Alzheimer Disease ; metabolism ; pathology ; psychology ; Amyloid beta-Protein Precursor ; genetics ; metabolism ; Animals ; Cyclic AMP Response Element-Binding Protein ; metabolism ; Cyclic AMP-Dependent Protein Kinases ; metabolism ; Disease Models, Animal ; Female ; Hippocampus ; metabolism ; pathology ; Humans ; Inflammation ; metabolism ; pathology ; psychology ; Male ; Maze Learning ; physiology ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurofibrillary Tangles ; metabolism ; pathology ; Plaque, Amyloid ; metabolism ; pathology ; psychology ; Presenilin-1 ; genetics ; metabolism ; Sex Characteristics ; Spatial Memory ; physiology ; p38 Mitogen-Activated Protein Kinases ; metabolism ; tau Proteins ; genetics ; metabolism

Hyperphosphorylated tau is the major protein component of neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). However, the mechanism underlying tau hyperphosphorylation is not fully understood. Here, we demonstrated that exogenously expressed wild-type human tau40 was detectable in the phosphorylated form at multiple AD-associated sites in cytoplasmic and nuclear fractions from HEK293 cells. Among these sites, tau phosphorylated at Thr205 and Ser214 was almost exclusively found in the nuclear fraction at the conditions used in the present study. With the intracellular tau accumulation, the Ca concentration was significantly increased in both cytoplasmic and nuclear fractions. Further studies using site-specific mutagenesis and pharmacological treatment demonstrated that phosphorylation of tau at Thr205 increased nuclear Ca concentration with a simultaneous increase in the phosphorylation of Ca/calmodulin-dependent protein kinase IV (CaMKIV) at Ser196. On the other hand, phosphorylation of tau at Ser214 did not significantly change the nuclear Ca/CaMKIV signaling. Finally, expressing calmodulin-binding protein-4 that disrupts formation of the Ca/calmodulin complex abolished the okadaic acid-induced tau hyperphosphorylation in the nuclear fraction. We conclude that the intracellular accumulation of phosphorylated tau, as detected in the brains of AD patients, can trigger nuclear Ca/CaMKIV signaling, which in turn aggravates tau hyperphosphorylation. Our findings provide new insights for tauopathies: hyperphosphorylation of intracellular tau and an increased Ca concentration may induce a self-perpetuating harmful loop to promote neurodegeneration.
Alzheimer Disease ; metabolism ; pathology ; Calcium ; metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 4 ; metabolism ; Cell Nucleus ; metabolism ; Enzyme Activation ; physiology ; HEK293 Cells ; Humans ; Neurons ; metabolism ; pathology ; Phosphorylation ; Signal Transduction ; physiology ; tau Proteins ; metabolism

OBJECTIVE: To investigate the effects of propofol combined with hypoxia on cognitive function of immature rats and the possible role of p38 pathway and tau protein in mediating such effects. METHODS: Ninety 7-day-old (P7) SD rats were randomized for daily intraperitoneal injection of propofol (50 mg/kg) or lipid emulsion (5.0 mL/kg) for 7 consecutive days. After each injection, the rats were placed in a warm box (38 ℃) with an oxygen concentration of 18% (hypoxia), 21% (normal air), or 50% (oxygen) until full recovery of the righting reflex. Another 90 P7 rats were similarly grouped and received intraperitoneal injections of p-p38 blocker (15 mg/kg) 30 min before the same treaments. The phosphorylated tau protein, total tau protein and p-p38 content in the hippocampus were detected using Western blotting. The spatial learning and memory abilities of the rats were evaluated with Morris water maze test. RESULTS: Compared with lipid emulsion, propofol injection resulted in significantly increased levels of p-p38, phosphorylated tau and total tau proteins in rats with subsequent hypoxic or normal air treatment ( < 0.05), but propofol with oxygen and injections of the blocker before propofol did not cause significant changes in the proteins. Without subsequent oxygenation, the rats receiving injections of propofol, with and without prior blocker injection, all showed significantly prolonged latency time and reduced platform-crossing times and third quadrant residence time compared with the corresponding lipid emulsion groups ( < 0.05). With oxygen treatment, the rats in propofoland blocker-treated groups showed no significant difference in the performance in Morris water maze test from the corresponding lipid emulsion group. The results of Morris water maze test differed significantly between blocker-propofol group and propofol groups irrespective of exposures to different oxygen levels ( < 0.05), but not between the lipid emulsion and blocker group pairs with exposures to different oxygen levels. CONCLUSIONS Propofol combined with hypoxia can affect the expression of tau protein through p38 pathway to impair the cognitive function of immature rats, in which oxygen plays a protective role.
Animals ; Cognitive Dysfunction ; etiology ; metabolism ; Hippocampus ; chemistry ; Hypnotics and Sedatives ; pharmacology ; Hypoxia, Brain ; complications ; metabolism ; MAP Kinase Signaling System ; Maze Learning ; drug effects ; physiology ; Memory ; drug effects ; physiology ; Propofol ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; tau Proteins ; analysis

OBJECTIVETo investigate the effect of hypobaric hypoxia (HH)on the cognitive function of mice and the phosphorylation of tau protein in mice brain.

METHODSForty male mice were randomly divided into 4 groups (n = 10): static control (control) group, 8 hours (8 h) group, 7 days(7 d) group and 28 days(28 d) group, which were exposed to simulated HH equivalent to 5 500 m in an animal decompression chamber for 0 hour, 8 hours, 7 days and 28 days, respectively. Cognitive performances were examined by open field and passive avoidance test, tan phosphorylation was assayed by Western blot.

RESULTSIn open field test,the group exposed in hypobaric hypoxia for 28 d showed lower mean velocity (P < 0.05), time in central zone (P < 0.05) was longer than control group. In passive avoidance test 28 d group presented worse performance in both latency time and number of mistakes (P < 0.05) compared with control group. Western blot showed that phosphorylated tau was increased significantly following exposure to HH for 7 d in cortex and 28 d in hippocampus (P < 0.05).

CONCLUSIONTau hyperphosphorylation in brain of mice may play a role in chronic HH-induced cognitive function impairment.

Animals ; Cerebral Cortex ; metabolism ; Disease Models, Animal ; Hippocampus ; metabolism ; Hypoxia ; metabolism ; physiopathology ; Male ; Maze Learning ; physiology ; Memory ; physiology ; Mice ; Phosphorylation ; tau Proteins ; metabolism

Progressive dementia is described as the first and most prominent symptom of Alzheimer's disease (AD), and hyperphosphorylation of microtubule associated Tau protein (MAPT) plays a key role in neurodegeneration and neuronal dysfunction in AD and other neurodegenerative diseases. This paper reviews several protein kinases and phosphatases which can phosphorylate/dephosphorylate Tau protein, and evaluates a therapeutic strategy based on targeted inhibition of Tau kinases and activation of Tau phosphatases.
Alzheimer Disease ; metabolism ; physiopathology ; Glycogen Synthase Kinase 3 ; antagonists & inhibitors ; metabolism ; Humans ; Neurodegenerative Diseases ; metabolism ; physiopathology ; Phosphoric Monoester Hydrolases ; metabolism ; Phosphorylation ; Protein Kinases ; metabolism ; tau Proteins ; chemistry ; metabolism ; physiology

In human prion diseases, phosphorylated-tau deposition has been described in a rare genetic form, Gerstmann-Straussler-Scheinker disease, but is not considered part of the neuropathological picture of Creutzfeldt-Jakob disease. To investigate the possible changes of tau and phosphorylated tau (Ser396/Ser404) in transmissible spongiform encephalopathies (TSEs), the expressions and transcriptions of above biological factors in the brain tissues of 263K- and 139A-infected hamsters were evaluated by Western blots and Real Time PCR, respectively, followed by quantitative analyses of immunoblot images and relative transcriptional levels compared with normal animals. The contents of total tau increased, but phosphorylated tau at Ser396 and Ser404 decreased, regardless of the types of scrapie agents and clinical incubations. Transcriptions of two tau isoforms were also markedly increased. These findings suggested that dephosphorylation of tau at Ser396/Ser404 was a illness-correlative phenomenon in TSEs. Alterations of tau and phosphorylated tau (Ser396/Ser404) were either intermediate or consequent events in TSE pathogenesis and proposed the potential linkage of these bioactive proteins with the pathogenesis of prion diseases.
Animals ; Blotting, Western ; Brain ; metabolism ; Cricetinae ; Gene Expression Regulation ; physiology ; Phosphorylation ; Polymerase Chain Reaction ; PrPSc Proteins ; pathogenicity ; Prion Diseases ; metabolism ; tau Proteins ; metabolism

The present study was aimed to investigate the effects of ginsenoside Rb1 on okadaic acid (OA)-induced Tau hyperphosphorylation in hippocampal neurons of Sparague-Dawley rat and to explore its possible mechanism. Animals were randomly divided into four groups. Group 1 received dimethysulphoxide (DMSO) injection (vehicle group), group 2 only received OA injection (OA group), group 3 was pretreated with Rb1 and then received OA injection (Rb1 pretreatment group), and the group 4 was an intact control group. The animals in group 3 were injected intraperitoneally with various doses of Rb1 at 5, 10, and 20 mg/kg (once a day for 14 d). On the thirteen day of pretreatment, animals in Rb1 pretreatment group as well as animals in OA group received a bolus injection of 0.483 microg of OA (1.5 microl of solution in DMSO) at right dorsal aspect of hippocampus to induce Tau hyperphosphrylation. The brains were harvested one day after the last treatment. In all groups, the morphology of neurofibrils, phosphorylation of Tau protein, and the activity of phosphatase 2A (PP2A) were investigated. In OA group, the Bielschowski's assay revealed darkened and uneven neurofibrils staining in the hippocampus. The immunohistochemistry results showed a significant increase in Thr(231) phosphorylation of Tau protein in OA group relative to the control group (P<0.01). OA injection also markedly decreased PP2A activity (P<0.01). Western blot confirmed Thr(231) phosphorylation of Tau protein and it also detected phosphorylation of Ser(396) of Tau protein. The animals with Rb1 pretreatment displayed even staining of neurofibrils and normal pattern of fiber organization. Rb1 pretreatment also attenuated Thr(231) and Ser(396) hyperphosphorylations of Tau protein, and restored PP2A activity compared to the OA group (P<0.01). These results indicate that OA-induced hyperphosphorylation of Tau protein in rat hippocampal neurons can be attenuated by the pretreatment of ginsenoside Rb1. These data also implicate that Rb1 has potential neuroprotective effects on Tau-related neuropathology.
Alzheimer Disease ; metabolism ; Animals ; Ginsenosides ; pharmacology ; Hippocampus ; cytology ; Male ; Neurons ; metabolism ; physiology ; Neuroprotective Agents ; pharmacology ; Okadaic Acid ; Phosphorylation ; drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; tau Proteins ; metabolism