scholarly journals Increased Cerebral Vascular Reactivity in the Tau Expressing rTg4510 Mouse: Evidence against the Role of Tau Pathology to Impair Vascular Health in Alzheimer's Disease

2015 ◽  
Vol 35 (3) ◽  
pp. 359-362 ◽  
Author(s):  
Jack A Wells ◽  
Holly E Holmes ◽  
James M O'Callaghan ◽  
Niall Colgan ◽  
Ozama Ismail ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Reactivity ◽  
Vascular Health ◽  
Tau Pathology ◽  
Vascular Abnormalities ◽  
Rtg4510 Mouse ◽  
Cortical Regions ◽  
Cerebral Vascular

Vascular abnormalities are a key feature of Alzheimer's disease (AD). Imaging of cerebral vascular reactivity (CVR) is a powerful tool to investigate vascular health in clinical populations although the cause of reduced CVR in AD patients is not fully understood. We investigated the specific role of tau pathology in CVR derangement in AD using the rTg4510 mouse model. We observed an increase in CVR in cortical regions with tau pathology. These data suggest that tau pathology alone does not produce the clinically observed decreases in CVR and implicates amyloid pathology as the dominant etiology of impaired CVR in AD patients.

scholarly journals Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

2021 ◽  
Vol 15 ◽  
Author(s):  
Guimei Zhang ◽  
Zicheng Wang ◽  
Huiling Hu ◽  
Meng Zhao ◽  
Li Sun
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Interventions ◽  
Tau Pathology ◽  
Age Related ◽  
Amyloid Accumulation ◽  
Pathophysiological Role ◽  
Inflammatory Drugs ◽  
Β Amyloid

Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.

scholarly journals TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading

2018 ◽  
Vol 215 (9) ◽  
pp. 2355-2377 ◽  
Author(s):  
Heidi Martini-Stoica ◽  
Allysa L. Cole ◽  
Daniel B. Swartzlander ◽  
Fading Chen ◽  
Ying-Wooi Wan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Connections ◽  
Transgenic Mouse Models ◽  
Reverse Effect ◽  
Tau Pathology ◽  
Transcription Factor Eb ◽  
Human Brains

The progression of tau pathology in Alzheimer’s disease follows a stereotyped pattern, and recent evidence suggests a role of synaptic connections in this process. Astrocytes are well positioned at the neuronal synapse to capture and degrade extracellular tau as it transits the synapse and hence could potentially have the ability to inhibit tau spreading and delay disease progression. Our study shows increased expression and activity of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, in response to tau pathology in both human brains with dementia and transgenic mouse models. Exogenous TFEB expression in primary astrocytes enhances tau fibril uptake and lysosomal activity, while TFEB knockout has the reverse effect. In vivo, induced TFEB expression in astrocytes reduces pathology in the hippocampus of PS19 tauopathy mice, as well as prominently attenuates tau spreading from the ipsilateral to the contralateral hippocampus in a mouse model of tau spreading. Our study suggests that astrocytic TFEB plays a functional role in modulating extracellular tau and the propagation of neuronal tau pathology in tauopathies such as Alzheimer’s disease.

THE ROLE OF COMPLEMENT C3 AND C3AR RECEPTOR IN TAU PATHOLOGY IN ALZHEIMER’S DISEASE

2017 ◽  
Vol 13 (7) ◽  
pp. P229
Author(s):  
Alexandra Litvinchuk ◽  
Ying-Wooi Wan ◽  
Allysa Cole ◽  
Fading Chen ◽  
Zhangdong Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Complement C3 ◽  
Tau Pathology

scholarly journals α-Synuclein modulates tau spreading in mouse brains

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Fares Bassil ◽  
Emily S. Meymand ◽  
Hannah J. Brown ◽  
Hong Xu ◽  
Timothy O. Cox ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Synergistic Effects ◽  
Tau Pathology ◽  
Vitro Data ◽  
In Vitro Data

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson’s disease (PD) and Alzheimer’s disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate–derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.

Neuroinflammation in Alzheimer’s disease: focus on NLRP1 and NLRP3 inflammasomes

2021 ◽  
Vol 22 ◽  
Author(s):  
Eliana Cristina de Brito Toscano ◽  
Natalia Pessoa Rocha ◽  
Beatriz Noele Azevedo Lopes ◽  
Claudia Kimie Suemoto ◽  
Antonio Lucio Teixeira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Experimental Models ◽  
Tau Pathology ◽  
Relevant Role ◽  
Nlrp3 Inflammasomes ◽  
Amyloid Cascade ◽  
Disease Focus

Background: Alzheimer’s disease (AD) is the main cause of dementia worldwide. The definitive diagnosis of AD is clinicopathological and based on the identification of cerebral deposition of amyloid β (Aβ) plaques and neurofibrillary tangles. However, the link between amyloid cascade and depositions of phosphorylated tau (p-tau) is still missing. In this scenario, inflammasomes might play a relevant role. Experimental models of AD have suggested that Aβ accumulation induces, through microglia, activation of the NLRP3 inflammasome. This activation contributes to the dissemination of Aβ and p-tau, as well as to hyperphosphorylation of tau. Also in experimental models, NLPR1 promoted neuronal pyroptosis. There are neither comprehensive neuropathologic characterization, nor clinicopathologic studies evaluating the NLRP1 and NLRP3 inflammasomes in subjects with AD. Objective: The current mini-review aims to summarize recent and promising findings on the role of NLRP1 and NLRP3 signaling in the pathophysiology of AD. We also sought to highlight the knowledge gap in patients with AD, mainly the lack of clinicopathologic studies on the interaction among inflammasomes, Aβ/tau pathology, and cognitive decline.

Transgenic mouse models for Alzheimer's disease: the role of GSK-3β in combined amyloid and tau-pathology

2006 ◽  
Vol 162 (10) ◽  
pp. 903-907 ◽  
Author(s):  
D. Muyllaert ◽  
D. Terwel ◽  
P. Borghgraef ◽  
H. Devijver ◽  
I. Dewachter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mouse ◽  
Mouse Models ◽  
Transgenic Mouse Models ◽  
Tau Pathology ◽  
Gsk 3Β

Role of TREM2 in Alzheimer's Disease and its Consequences on β- Amyloid, Tau and Neurofibrillary Tangles

2020 ◽  
Vol 16 (13) ◽  
pp. 1216-1229 ◽  
Author(s):  
Anurag K. Singh ◽  
Gaurav Mishra ◽  
Anand Maurya ◽  
Rajendra Awasthi ◽  
Komal Kumari ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Tau Pathology ◽  
Functional Roles ◽  
Age Related ◽  
Β Amyloid ◽  
The Impact ◽  
Neuronal Stress

: Alzheimer's Disease (AD) is age-related neurodegenerative disorder recognized by a steadily gradual cognitive decline that has devastating personal and socioeconomic implications. Recently, some genetic factors for AD have been identified which attracted wide attention of researchers in different areas of AD biology and possible new therapeutic targets. Alternative forms of triggering receptor expressed on myeloid cells 2 (TREM2) genes are examples of such risk factors, which contribute higher risk for developing AD. Comprehending TREM2 function pledge to provide salient insight into how neuroinflammation contributes to AD pathology. The dearth of microglial TREM2 shepherd to augmented tau pathology is couple with frequent enhancement of activated neuronal stress kinases. The involvement of TREM2 in the regulation of tau-associated innate immune response of the CNS has clearly demonstrated through these findings. However, whether decrease level of TREM2 assists pathology of tau through changed clearance and pathological escalation of tau or through direct contact between microglia and neuron and any alternative possible mechanisms need to examine. This review briefly summarizes distinct functional roles of TREM2 in AD pathology and highlights the TREM2 gene regulation. We have also addressed the impact of TREM2 on β-amyloid plaques and tau pathology in Alzheimer’s disease.

scholarly journals Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer’s disease

2020 ◽  
Vol 52 (8) ◽  
pp. 1275-1287
Author(s):  
Seong Su Kang ◽  
Eun Hee Ahn ◽  
Keqiang Ye
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Strategy ◽  
Senile Plaques ◽  
Tau Pathology ◽  
Disease Modifying ◽  
Tau Aggregation ◽  
The Brain ◽  
Insight Into

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease with age as a major risk factor. AD is the most common dementia with abnormal structures, including extracellular senile plaques and intraneuronal neurofibrillary tangles, as key neuropathologic hallmarks. The early feature of AD pathology is degeneration of the locus coeruleus (LC), which is the main source of norepinephrine (NE) supplying various cortical and subcortical areas that are affected in AD. The spread of Tau deposits is first initiated in the LC and is transported in a stepwise manner from the entorhinal cortex to the hippocampus and then to associative regions of the neocortex as the disease progresses. Most recently, we reported that the NE metabolite DOPEGAL activates delta-secretase (AEP, asparagine endopeptidase) and triggers pathological Tau aggregation in the LC, providing molecular insight into why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in the disease and how δ-secretase mediates the spread of Tau pathology to the rest of the brain. This review summarizes our current understanding of the crucial role of δ-secretase in driving and spreading AD pathologies by cleaving multiple critical players, including APP and Tau, supporting that blockade of δ-secretase may provide an innovative disease-modifying therapeutic strategy for treating AD.

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