Secernin-1 is a novel phosphorylated tau binding protein that accumulates in Alzheimer’s disease and not in other tauopathies

AbstractWe recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer’s disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT, n = 21; Moderate NFT, n = 22; Low/No NFT, n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and AD-related neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis – Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick’s disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Co-immunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.

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Progressive Supranuclear Palsy: A Review of Co-existing Neurodegeneration

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100009392 ◽

2008 ◽

Vol 35 (5) ◽

pp. 602-608 ◽

Cited By ~ 12

Author(s):

J Keith-Rokosh ◽

L C Ang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Neurodegenerative Diseases ◽

Progressive Supranuclear Palsy ◽

Lewy Bodies ◽

Corticobasal Degeneration ◽

Pathological Changes ◽

Subcortical Regions ◽

Argyrophilic Grains

Objectives:The neuropathological findings of 32 progressive supranuclear palsy (PSP) cases over a period of 17 years were reviewed.Results:Of the 26 cases with adequate clinical data, 20 patients either presented with cognitive dysfunction or developed a cognitive impairment subsequently during the course of the disease. Co-existing changes of argyrophilic grains and corticobasal degeneration (CBD) were found in 28% and 32% of the cases respectively. Alzheimer-related pathology was found in 69% of cases but only 18.75% of cases fulfilled the consortium to establish a registry for Alzheimer's disease (CERAD) criteria for either definite or probable Alzheimer's disease. Lewy bodies were noted in four cases (12.5%), all in the subcortical regions. Only seven cases of PSP showed no pathological evidence of other co-existing neurodegenerative diseases. The severity of the cerebrovascular pathology in this cohort was insufficient to explain any clinical symptomatology.Conclusions:As in previous studies, this study has demonstrated the frequent co-existence of pathological changes usually noted in other neurodegenerative diseases in PSP. Whether these coexisting pathological changes contribute to the cognitive impairment in PSP remains uncertain.

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Elevated age-related cortical iron, ferritin and amyloid plaques in APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease

Physiological Research ◽

10.33549/physiolres.934383 ◽

2019 ◽

pp. S445-S451 ◽

Cited By ~ 2

Author(s):

H. Svobodová ◽

D. Kosnáč ◽

Z. Balázsiová ◽

H. Tanila ◽

P.O. Miettinen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Plaques ◽

Amyloid Plaque ◽

Free Iron ◽

Model Of Alzheimer’S Disease ◽

Age Related ◽

Concentration Changes ◽

The Brain ◽

Important Marker

Iron is very important element for functioning of the brain. Its concentration changes with aging the brain or during disease. The aim of our work was the histological examination of content of ferritin and free iron (unbound) in brain cortex in association with Aβ plaques from their earliest stages of accumulation in amyloid plaque forming APP/PS1 transgenic mice. Light microscopy revealed the onset of plaques formation at 8-monthage. Detectable traces of free iron and no ferritin were found around plaques at this age, while the rate of their accumulation in and around Aβ plaques was elevated at 13 months of age. Ferritin accumulated mainly on the edge of Aβ plaques, while the smaller amount of free iron was observed in the plaque-free tissue, as well as in and around Aβ plaques. We conclude that free iron and ferritin accumulation follows the amyloid plaques formation. Quantification of cortical iron and ferritin content can be an important marker in the diagnosis of Alzheimer’s disease.

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Neurochemical Diversity of Dystrophic Neurites in the Early and Late Stages of Alzheimer's Disease

Experimental Neurology ◽

10.1006/exnr.1998.7010 ◽

1999 ◽

Vol 156 (1) ◽

pp. 100-110 ◽

Cited By ~ 93

Author(s):

Tracey C. Dickson ◽

Carolyn E. King ◽

Graeme H. McCormack ◽

James C. Vickers

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dystrophic Neurites ◽

Late Stages

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Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Cells ◽

10.3390/cells9010150 ◽

2020 ◽

Vol 9 (1) ◽

pp. 150 ◽

Cited By ~ 20

Author(s):

Qian Cai ◽

Yu Young Jeong

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Cellular Energy ◽

Age Related ◽

Mitochondrial Turnover ◽

Neuronal Functions ◽

Lateral Sclerosis

Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Mitochondria are the main cellular energy powerhouses, supplying most of ATP by oxidative phosphorylation, which is required to fuel essential neuronal functions. Efficient removal of aged and dysfunctional mitochondria through mitophagy, a cargo-selective autophagy, is crucial for mitochondrial maintenance and neuronal health. Mechanistic studies into mitophagy have highlighted an integrated and elaborate cellular network that can regulate mitochondrial turnover. In this review, we provide an updated overview of the recent discoveries and advancements on the mitophagy pathways and discuss the molecular mechanisms underlying mitophagy defects in Alzheimer’s disease and other age-related neurodegenerative diseases, as well as the therapeutic potential of mitophagy-enhancing strategies to combat these disorders.

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The Contribution of Epigenetic Inheritance Processes on Age-Related Cognitive Decline and Alzheimer’s Disease

Epigenomes ◽

10.3390/epigenomes5020015 ◽

2021 ◽

Vol 5 (2) ◽

pp. 15

Author(s):

Aina Bellver-Sanchis ◽

Mercè Pallàs ◽

Christian Griñán-Ferré

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Cognitive Decline ◽

Association Studies ◽

Cognitive Status ◽

Human Populations ◽

Genome Wide Association Studies ◽

Age Related ◽

Age Related Cognitive Decline

During the last years, epigenetic processes have emerged as important factors for many neurodegenerative diseases, such as Alzheimer’s disease (AD). These complex diseases seem to have a heritable component; however, genome-wide association studies failed to identify the genetic loci involved in the etiology. So, how can these changes be transmitted from one generation to the next? Answering this question would allow us to understand how the environment can affect human populations for multiple generations and explain the high prevalence of neurodegenerative diseases, such as AD. This review pays particular attention to the relationship among epigenetics, cognition, and neurodegeneration across generations, deepening the understanding of the relevance of heritability in neurodegenerative diseases. We highlight some recent examples of EI induced by experiences, focusing on their contribution of processes in learning and memory to point out new targets for therapeutic interventions. Here, we first describe the prominent role of epigenetic factors in memory processing. Then, we briefly discuss aspects of EI. Additionally, we summarize evidence of how epigenetic marks inherited by experience and/or environmental stimuli contribute to cognitive status offspring since better knowledge of EI can provide clues in the appearance and development of age-related cognitive decline and AD.

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The autophagy activator Spermidine ameliorates Alzheimer’s disease pathology and neuroinflammation in mice

10.1101/2020.12.27.424477 ◽

2020 ◽

Author(s):

Kiara Freitag ◽

Nele Sterczyk ◽

Julia Schulz ◽

Judith Houtman ◽

Lara Fleck ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Inflammatory Response ◽

Glial Cells ◽

Oral Treatment ◽

Small Body ◽

Phosphorylated Tau ◽

Inflammatory Processes ◽

Late Stages ◽

Inflammasome Activity

AbstractDeposition of amyloid beta (Aβ) and phosphorylated Tau along with microglia- and astrocyte-mediated neuroinflammation are prominent pathogeneic features of Alzheimer’s Disease (AD). In recent years, impairment of autophagy has also been shown to contribute to AD progression. Here, we provide evidence that oral treatment of amyloid-prone AD-like APPPS1 mice with the autophagy activator Spermidine, a small body-endogenous polyamine often used as dietary supplement, decreased neuroinflammation and reduced neurotoxic soluble Aβ at both early and late stages of AD. Mechanistically, Spermidine induced autophagy in microglia as well as in astrocytes, which subsequently impacted TLR3- and TLR4-mediated inflammatory processes by decreasing cytotoxicity, inflammasome activity and NF-κB signalling. Our data highlight that autophagy targets the inflammatory response of glial cells and emphasize the potential of orally administered autophagy-activating drugs such as Spermidine to interfere with AD progression.

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Potential Roles of Sestrin2 in Alzheimer’s Disease: Antioxidation, Autophagy Promotion, and Beyond

Biomedicines ◽

10.3390/biomedicines9101308 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1308

Author(s):

Shang-Der Chen ◽

Jenq-Lin Yang ◽

Yi-Heng Hsieh ◽

Tsu-Kung Lin ◽

Yi-Chun Lin ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Memory Loss ◽

Oxygen Species ◽

Mechanistic Target Of Rapamycin ◽

Cell Cycle Reentry ◽

Age Related ◽

Reduce Activity

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease. It presents with progressive memory loss, worsens cognitive functions to the point of disability, and causes heavy socioeconomic burdens to patients, their families, and society as a whole. The underlying pathogenic mechanisms of AD are complex and may involve excitotoxicity, excessive generation of reactive oxygen species (ROS), aberrant cell cycle reentry, impaired mitochondrial function, and DNA damage. Up to now, there is no effective treatment available for AD, and it is therefore urgent to develop an effective therapeutic regimen for this devastating disease. Sestrin2, belonging to the sestrin family, can counteract oxidative stress, reduce activity of the mammalian/mechanistic target of rapamycin (mTOR), and improve cell survival. It may therefore play a crucial role in neurodegenerative diseases like AD. However, only limited studies of sestrin2 and AD have been conducted up to now. In this article, we discuss current experimental evidence to demonstrate the potential roles of sestrin2 in treating neurodegenerative diseases, focusing specifically on AD. Strategies for augmenting sestrin2 expression may strengthen neurons, adapting them to stressful conditions through counteracting oxidative stress, and may also adjust the autophagy process, these two effects together conferring neuronal resistance in cases of AD.

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Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.662242 ◽

2021 ◽

Vol 15 ◽

Author(s):

Xin Zhang ◽

Nadine Alshakhshir ◽

Liqin Zhao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Brain Aging ◽

Redox Homeostasis ◽

Critical Role ◽

Glycolytic Flux ◽

Glycolytic Metabolism ◽

Age Related ◽

Brain Resilience

Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

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PET/SPECT imaging agents for neurodegenerative diseases

Chemical Society Reviews ◽

10.1039/c3cs60430f ◽

2014 ◽

Vol 43 (19) ◽

pp. 6683-6691 ◽

Cited By ~ 71

Author(s):

Lin Zhu ◽

Karl Ploessl ◽

Hank F. Kung

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Neurodegenerative Diseases ◽

Pet Imaging ◽

Amyloid Plaque ◽

Spect Imaging ◽

Imaging Agents ◽

Plaque Deposition ◽

Β Amyloid

Amyvid/PET imaging of a living brain detects β-amyloid plaque deposition, a risk factor for developing Alzheimer's disease.

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Transitions in metabolic and immune systems from pre-menopause to post-menopause: implications for age-associated neurodegenerative diseases

F1000Research ◽

10.12688/f1000research.21599.1 ◽

2020 ◽

Vol 9 ◽

pp. 68 ◽

Cited By ~ 6

Author(s):

Yiwei Wang ◽

Aarti Mishra ◽

Roberta Diaz Brinton

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Aging Process ◽

Brain Aging ◽

Hormone Replacement ◽

Low Grade ◽

Chronological Aging ◽

Age Related ◽

Female Brain

The brain undergoes two aging programs: chronological and endocrinological. This is particularly evident in the female brain, which undergoes programs of aging associated with reproductive competency. Comprehensive understanding of the dynamic metabolic and neuroinflammatory aging process in the female brain can illuminate windows of opportunities to promote healthy brain aging. Bioenergetic crisis and chronic low-grade inflammation are hallmarks of brain aging and menopause and have been implicated as a unifying factor causally connecting genetic risk factors for Alzheimer’s disease and other neurodegenerative diseases. In this review, we discuss metabolic phenotypes of pre-menopausal, peri-menopausal, and post-menopausal aging and their consequent impact on the neuroinflammatory profile during each transition state. A critical aspect of the aging process is the dynamic metabolic neuro-inflammatory profiles that emerge during chronological and endocrinological aging. These dynamic systems of biology are relevant to multiple age-associated neurodegenerative diseases and provide a therapeutic framework for prevention and delay of neurodegenerative diseases of aging. While these findings are based on investigations of the female brain, they have a broader fundamental systems of biology strategy for investigating the aging male brain. Molecular characterization of alterations in fuel utilization and neuroinflammatory mechanisms during these neuro-endocrine transition states can inform therapeutic strategies to mitigate the risk of Alzheimer’s disease in women. We further discuss a precision hormone replacement therapy approach to target symptom profiles during endocrine and chronological aging to reduce risk for age-related neurodegenerative diseases.

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