Dataset Information

SUMO1 impact on Alzheimer disease pathology in an amyloid-depositing mouse model.

ABSTRACT: Small ubiquitin-related modifiers (SUMOs) conjugated or bound to target proteins can affect protein trafficking, processing and solubility. SUMOylation has been suggested to play a role in the amyloid plaque and neurofibrillary tangle pathology of Alzheimer disease (AD) and related neurodegenerative diseases. The current study examines the impact of SUMO1 on processing of the amyloid precursor protein (APP) leading to the production and deposition of the amyloid-β (Aβ) peptide. An in vivo model of these pathways was developed by the generation of double transgenic mice over-expressing human SUMO1 and a mutant APP. The SUMO1-APP transgenics displayed normal APP processing but, at later ages, exhibited increased insoluble Aβ and plaque density accompanied by increased dendritic spine loss, more pronounced synaptic and cognitive deficits. These findings suggest a potential impairment in Aβ clearance as opposed to increased amyloid production. Examination of microglia indicated a reduction in the SUMO1-APP transgenics which is a possible mechanism for the SUMO1-mediated increase in amyloid load. These findings suggest an indirect activity of SUMO1 possibly in the removal of Aβ plaques rather than a direct impact on amyloid generation.

SUBMITTER: Knock E

PROVIDER: S-EPMC9024178 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SUMO1 impact on Alzheimer disease pathology in an amyloid-depositing mouse model.

Knock Erin E Matsuzaki Shinsuke S Takamura Hironori H Satoh Kanayo K Rooke Grace G Han Kyung K Zhang Hong H Staniszewski Agnieszka A Katayama Taiichi T Arancio Ottavio O Fraser Paul E PE

Neurobiology of disease 20171205

Small ubiquitin-related modifiers (SUMOs) conjugated or bound to target proteins can affect protein trafficking, processing and solubility. SUMOylation has been suggested to play a role in the amyloid plaque and neurofibrillary tangle pathology of Alzheimer disease (AD) and related neurodegenerative diseases. The current study examines the impact of SUMO1 on processing of the amyloid precursor protein (APP) leading to the production and deposition of the amyloid-β (Aβ) peptide. An in vivo model ...[more]

PMID: 29217476

Similar Datasets

Project description:BackgroundAccumulation and deposition of ?-amyloid peptides (A?) in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Besides the parenchymal pathology, A? is known to undergo active transport across the blood-brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty A? transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer's disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized A? and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background.ResultsIntroduction of the Dutch mutation results in robust CAA and parenchymal A? pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology.ConclusionsOur study reveals a direct and positive link between vascular and parenchymal A?; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal A? pathology and behavioral deficits in the absence of APP overexpression.

Project description:ImportanceThe accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging.ObjectiveTo assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content.Design, setting, and participantsMagnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals.Main outcomes and measuresAutomated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction.ResultsThe mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/β-amyloid 42, suggesting that phosphorylated tau 181/β-amyloid 42 levels modulate age-related changes in myelin water fraction.Conclusions and relevanceThese findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials.

Project description:BackgroundTransgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral beta-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.Methodology/principal findingsThe transgenic mouse line (ARTE10) was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APP(swe)) and the M146V mutated presenilin 1 (PS1) both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral beta-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a gamma-secretase inhibitor we show a dose dependent reduction of soluble amyloid beta levels in the brain.ConclusionsARTE10 mice develop a cerebral beta-amyloidosis closely resembling the beta-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for the use in target validation and for evaluating potential diagnostic or therapeutic agents targeting the amyloid pathology of AD.

Dataset Information

SUMO1 impact on Alzheimer disease pathology in an amyloid-depositing mouse model.

Publications

SUMO1 impact on Alzheimer disease pathology in an amyloid-depositing mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets