The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease

Background: Studies have suggested that cognitive impairment in Alzheimer’s disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice. Objective: In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice. Results: It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus. Conclusion: These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.

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Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ1–42 synaptotoxicity

The Journal of Cell Biology ◽

10.1083/jcb.201701045 ◽

2017 ◽

Vol 216 (10) ◽

pp. 3161-3178 ◽

Cited By ~ 20

Author(s):

Xiaoyi Qu ◽

Feng Ning Yuan ◽

Carlo Corona ◽

Silvia Pasini ◽

Maria Elena Pero ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Axonal Transport ◽

Dendritic Spines ◽

Posttranslational Modifications ◽

Hippocampal Neurons ◽

Neuronal Damage ◽

Driving Factors ◽

Hyperphosphorylated Tau ◽

Tau Hyperphosphorylation

Oligomeric Amyloid β1–42 (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

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Testosterone modulation of dendritic spines of somatosensory cortical pyramidal neurons

Brain Structure and Function ◽

10.1007/s00429-012-0465-7 ◽

2013 ◽

Vol 218 (6) ◽

pp. 1407-1417 ◽

Cited By ~ 11

Author(s):

Jeng-Rung Chen ◽

Tsyr-Jiuan Wang ◽

Seh-Hong Lim ◽

Yueh-Jan Wang ◽

Guo-Fang Tseng

Keyword(s):

Dendritic Spines ◽

Pyramidal Neurons ◽

Cortical Pyramidal Neurons

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Alzheimer’s Disease: From Amyloid to Autoimmune Hypothesis

The Neuroscientist ◽

10.1177/1073858420908189 ◽

2020 ◽

Vol 26 (5-6) ◽

pp. 455-470

Author(s):

Yuri I. Arshavsky

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune System ◽

Pyramidal Neurons ◽

Adaptive Immune System ◽

Memory Formation ◽

Autoimmune Response ◽

Prevention And Treatment ◽

Ad Prevention ◽

Clinical Verification

Although Alzheimer’s disease (AD) was described over a century ago, there are no effective approaches to its prevention and treatment. Such a slow progress is explained, at least in part, by our incomplete understanding of the mechanisms underlying the pathogenesis of AD. Here, I champion a hypothesis whereby AD is initiated on a disruption of the blood-brain barrier (BBB) caused by either genetic or non-genetic risk factors. The BBB disruption leads to an autoimmune response against pyramidal neurons located in the allo- and neocortical structures involved in memory formation and storage. The response caused by the adaptive immune system is not strong enough to directly kill neurons but may be sufficient to make them selectively vulnerable to neurofibrillary pathology. This hypothesis is based on the recent data showing that memory formation is associated with epigenetic chromatin modifications and, therefore, may be accompanied by expression of memory-specific proteins recognized by the immune system as “non-self” antigens. The autoimmune hypothesis is testable, and I discuss potential ways for its experimental and clinical verification. If confirmed, this hypothesis can radically change therapeutic approaches to AD prevention and treatment.

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Aβ mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease

Journal of Neuroscience ◽

10.1523/jneurosci.2127-17.2017 ◽

2017 ◽

Vol 38 (5) ◽

pp. 1085-1099 ◽

Cited By ~ 39

Author(s):

Reddy Peera Kommaddi ◽

Debajyoti Das ◽

Smitha Karunakaran ◽

Siddharth Nanguneri ◽

Deepti Bapat ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Deficits ◽

Dendritic Spines

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PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1606171113 ◽

2016 ◽

Vol 113 (43) ◽

pp. 12292-12297 ◽

Cited By ~ 46

Author(s):

Loukia Katsouri ◽

Yau M. Lim ◽

Katrin Blondrath ◽

Ioanna Eleftheriadou ◽

Laura Lombardero ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pyramidal Neurons ◽

Lentiviral Vector ◽

Disease Model ◽

Amyloid Β ◽

Neuronal Loss ◽

Peroxisome Proliferator ◽

Neuroprotective Effects ◽

Peroxisome Proliferator Activated Receptor

Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.

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The Expression of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) in Hippocampal Arterioles Declines During Progression of Alzheimer’s Disease

Cerebral Cortex Communications ◽

10.1093/texcom/tgaa031 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Kelley E Anderson ◽

Thomas A Bellio ◽

Emily Aniskovich ◽

Stephanie L Adams ◽

Jan Krzysztof Blusztajn ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Vessels ◽

Pyramidal Neurons ◽

Brain Parenchyma ◽

Amyloid Angiopathy ◽

Type I ◽

Clinical Dementia Rating ◽

Activin Receptor ◽

Receptor Like Kinase

Abstract Cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD)—deposition of beta amyloid (Aβ) within the walls of cerebral blood vessels—typically accompanies Aβ buildup in brain parenchyma and causes abnormalities in vessel structure and function. We recently demonstrated that the immunoreactivity of activin receptor-like kinase 1 (ALK1), the type I receptor for circulating BMP9/BMP10 (bone morphogenetic protein) signaling proteins, is reduced in advanced, but not early stages of AD in CA3 pyramidal neurons. Here we characterize vascular expression of ALK1 in the context of progressive AD pathology accompanied by amyloid angiopathy in postmortem hippocampi using immunohistochemical methods. Hippocampal arteriolar wall ALK1 signal intensity was 35% lower in AD patients (Braak and Braak Stages IV and V [BBIV-V]; clinical dementia rating [CDR1-2]) as compared with subjects with early AD pathologic changes but either cognitively intact or with minimal cognitive impairment (BBIII; CDR0-0.5). The intensity of Aβ signal in arteriolar walls was similar in all analyzed cases. These data suggest that, as demonstrated previously for specific neuronal populations, ALK1 expression in blood vessels is also vulnerable to the AD pathophysiologic process, perhaps related to CAA. However, cortical arterioles may remain responsive to the ALK1 ligands, such as BMP9 and BMP10 in early and moderate AD.

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