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Berlin Brandenburg

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  • 1
    Language: English
    In: Science (New York, N.Y.), 22 September 2006, Vol.313(5794), pp.1781-4
    Description: Protein aggregation is an established pathogenic mechanism in Alzheimer's disease, but little is known about the initiation of this process in vivo. Intracerebral injection of dilute, amyloid-beta (Abeta)-containing brain extracts from humans with Alzheimer's disease or beta-amyloid precursor protein (APP) transgenic mice induced cerebral beta-amyloidosis and associated pathology in APP transgenic mice in a time- and concentration-dependent manner. The seeding activity of brain extracts was reduced or abolished by Abeta immunodepletion, protein denaturation, or by Abeta immunization of the host. The phenotype of the exogenously induced amyloidosis depended on both the host and the source of the agent, suggesting the existence of polymorphic Abeta strains with varying biological activities reminiscent of prion strains.
    Keywords: Amyloid Beta-Peptides -- Administration & Dosage ; Amyloid Beta-Protein Precursor -- Administration & Dosage ; Amyloidosis -- Metabolism ; Brain Diseases -- Metabolism ; Hippocampus -- Chemistry
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Trends in Neurosciences, October 2015, Vol.38(10), pp.659-668
    Description: Several recent genome-wide association studies (GWAS) in patients with neurodegenerative disorders have shed new light on the brain immune system, suggesting that it plays a pivotal role in disease pathogenesis. Mononuclear phagocytes are blatantly involved in Alzheimer's disease (AD) of the central nervous system (CNS), but the specific functions of resident microglia, perivascular or meningeal macrophages, and circulating myeloid cells have not yet been fully resolved. Next-generation sequencing, high-throughput immune profiling technologies, and novel genetic tools have recently revolutionized the characterization of innate immune responses during AD. These studies advocate selective and non-redundant roles for myeloid subsets, which could be a target for novel disease-modifying therapies in AD. Myeloid cells differ in their kinetics (long-lived versus short-lived) and localization. This should be taken into account when targeting myeloid cells during neurodegenerative diseases. Microglia are recruited to and cluster around newly formed Aβ plaques, indicating that they are not directly involved in the initial stages of amyloid plaque formation. Microglia are phagocytic cells in the brain equipped with several receptors that play a role in the clearance of Aβ. Downregulation of these immune-receptors results in compromised phagocytotic capacity of microglia. Morphological alterations such as dystrophic (senescent) microglia have been observed in the aged human and AD brain. Emerging data suggest that microglia deteriorate with age and are dysfunctional during AD.
    Keywords: Microglia ; Yolk Sac ; Neurodegeneration ; Cx3cr1 ; Macrophage ; Alzheimer'S Disease ; Medicine ; Anatomy & Physiology
    ISSN: 0166-2236
    E-ISSN: 1878-108X
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  • 3
    In: Nature, 2008, Vol.451(7179), p.720
    Description: Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    In: Nature Neuroscience, 2013, Vol.16(5), p.580
    Description: Astrocytes are thought to have important roles after brain injury, but their behavior has largely been inferred from postmortem analysis. To examine the mechanisms that recruit astrocytes to sites of injury, we used in vivo two-photon laser- scanning microscopy to follow the response of GFP-labeled astrocytes in the adult mouse cerebral cortex over several weeks after acute injury. Live imaging revealed a marked heterogeneity in the reaction of individual astrocytes, with one subset retaining their initial morphology, another directing their processes toward the lesion, and a distinct subset located at juxtavascular sites proliferating. Although no astrocytes actively migrated toward the injury site, selective proliferation of juxtavascular astrocytes was observed after the introduction of a lesion and was still the case, even though the extent was reduced, after astrocyte-specific deletion of the RhoGTPase Cdc42. Thus, astrocyte recruitment after injury relies solely on proliferation in a specific niche.
    Keywords: Astrocytes – Physiological Aspects ; Astrocytes – Health Aspects ; Scanning Microscopy – Methods ; Medical Lasers – Usage ; Cerebral Cortex – Physiological Aspects ; Cerebral Cortex – Health Aspects;
    ISSN: 1097-6256
    E-ISSN: 1546-1726
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  • 5
    In: EMBO Journal, 17 January 2018, Vol.37(2), pp.167-182
    Description: Alzheimer's disease () is characterized by severe neuronal loss as well as the accumulation of amyloid‐β (Aβ), which ultimately leads to plaque formation. Although there is now a general agreement that the aggregation of Aβ can be initiated by prion‐like seeding, the impact and functional consequences of induced Aβ deposits (Aβ seeding) on neurons still remain open questions. Here, we find that Aβ seeding, representing early stages of plaque formation, leads to a dramatic decrease in proliferation and neurogenesis in two transgenic mouse models. We further demonstrate that neuronal cell death occurs primarily in the vicinity of induced Aβ deposits culminating in electrophysiological abnormalities. Notably, environmental enrichment and voluntary exercise not only revives adult neurogenesis and reverses memory deficits but, most importantly, prevents Aβ seeding by activated, phagocytic microglia cells. Our work expands the current knowledge regarding Aβ seeding and the consequences thereof and attributes microglia an important role in diminishing Aβ seeding by environmental enrichment. Prion‐like Aβ seeding impairs neurogenesis and enhances cell death leading to electrophysiological abnormalities and memory deficits. Environmental stimuli reverse this memory impairment and diminish Aβ seeding by activating phagocytic microglia. Seed‐induced Aβ deposits directly affect adult neurogenesis and induces cell death leading to impaired memory. Housing the mice in an environmental enrichment potently reverses neurogenic and memory deficits. Activated phagocytic microglia prevent Aβ seeding under enriched environmental condition. Environmental stimuli and voluntary exercise, known to ameliorate dementia rescue adult neurogenesis in transgenic mouse models by activating phagocytic microglia to reduce amyloid‐β seeding.
    Keywords: Adult Neurogenesis ; Alzheimer'S Disease ; Aβ Seeding ; Environmental Enrichment ; Microglia
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 6
    Language: English
    In: Frontiers in psychiatry, 2012, Vol.3, pp.26
    Description: Alzheimer's disease (AD) is a protein conformational disorder characterized by two major neuropathological features: extracellular accumulations of amyloid-β peptides in the form of plaques and intracellular tangles, consisting of hyperphosphorylated tau proteins. Several morphological and functional changes are associated with these lesions in the diseased brain, such as dendritic and synaptic alterations, as well as microglial and astroglial recruitment and their activation. The availability of transgenic mouse models that mimic key aspects of the disease in conjunction with recent advances in two-photon imaging facilitate the study of fundamental aspects of AD pathogenesis and allow for longitudinally monitoring the efficacy of therapeutic interventions. Here, we review the ambitious efforts to understand the relationship between the main neuropathological hallmarks of AD and their associated structural and functional abnormalities by means of in vivo two-photon imaging.
    Keywords: Caa ; Amyloid Plaques ; Calcium Imaging ; Dendritic Spines ; Glial Cells ; Microglia ; Multiphoton Imaging ; Neurofibrillary Tangles
    E-ISSN: 1664-0640
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  • 7
    Language: English
    In: Nature medicine, July 2015, Vol.21(7), pp.802-7
    Description: Amyloid-β (Aβ) plaques and α-synuclein (α-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB) and in more than 50% of AD cases. Their brains display substantial α-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Aβ plaques. Several studies report binding and coaggregation of Aβ and α-syn, yet the precise role of α-syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of α-syn-containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695(KM670/671NL) and PSEN1(L166P) under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, α-syn failed to cross-seed Aβ plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCA(A30P) (referred to here as 'APPPS1 × [A30P]aSYN' double-transgenic mice). This was accompanied by increased Aβ levels in cerebrospinal fluid despite unchanged overall Aβ levels. Notably, the seeding activity of Aβ-containing brain homogenates was considerably reduced by α-syn, and Aβ deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Aβ and α-syn leads to inhibition of Aβ deposition and to reduced plaque formation.
    Keywords: Amyloid Beta-Peptides -- Metabolism ; Plaque, Amyloid -- Metabolism ; Alpha-Synuclein -- Metabolism
    ISSN: 10788956
    E-ISSN: 1546-170X
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  • 8
    Language: English
    In: Frontiers in Cellular Neuroscience, 01 December 2018, Vol.12
    Description: Synapse loss has detrimental effects on cellular communication, leading to network disruptions within the central nervous system (CNS) such as in Alzheimer’s disease (AD). AD is characterized by a progressive decline of memory function, cognition, neuronal and synapse loss. The two main neuropathological...
    Keywords: Alzheimer’s Disease ; Amyloid Plaques ; Glial Cells ; Synapse Loss ; Microglia ; Astrocytes ; Medicine
    E-ISSN: 1662-5102
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  • 9
    Language: English
    In: Molecular Neurodegeneration, 01 March 2011, Vol.6(1), p.22
    Description: Abstract Background Immunization against amyloid-β (Aβ), the peptide that accumulates in the form of senile plaques and in the cerebrovasculature in Alzheimer's disease (AD), causes a dramatic immune response that prevents plaque formation and clears accumulated Aβ in transgenic mice. In a...
    Keywords: Anatomy & Physiology
    ISSN: 1750-1326
    E-ISSN: 1750-1326
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 11 January 2005, Vol.102(2), pp.479-84
    Description: Diffusion parameters of the extracellular space (ECS) are changed in many brain pathologies, disturbing synaptic as well as extrasynaptic "volume" transmission, which is based on the diffusion of neuroactive substances in the ECS. Amyloid deposition, neuronal loss, and disturbed synaptic transmission are considered to be the main causes of Alzheimer's disease dementia. We studied diffusion parameters in the cerebral cortex of transgenic APP23 mice, which develop a pathology similar to Alzheimer's disease. The real-time tetramethylammonium (TMA) method and diffusion-weighted MRI were used to measure the ECS volume fraction (alpha = ECS volume/total tissue volume) and the apparent diffusion coefficients (ADCs) of TMA (ADC(TMA)), diffusing exclusively in the ECS and of water (ADC(W)). Measurements were performed in vivo in 6-, 8-, and 17- to 25-month-old hemizygous APP23 male and female mice and age-matched controls. In all 6- to 8-month-old APP23 mice, the mean ECS volume fraction, ADC(TMA), and ADC(W) were not significantly different from age-matched controls (alpha = 0.20 +/- 0.01; ADC(TMA), 580 +/- 16 microm(2).s(-1); ADC(W), 618 +/- 19 microm(2).s(-1)). Aging in 17- to 25-month-old controls was accompanied by a decrease in ECS volume fraction and ADC(W), significantly greater in females than in males, but no changes in ADC(TMA). ECS volume fraction increased (0.22 +/- 0.01) and ADC(TMA) decreased (560 +/- 7 microm(2).s(-1)) in aged APP23 mice. The impaired navigation observed in these animals in the Morris water maze correlated with their plaque load, which was twice as high in females (20%) as in males (10%) and may, together with changed ECS diffusion properties, account for the impaired extrasynaptic transmission and spatial cognition observed in old transgenic females.
    Keywords: Disease Models, Animal ; Alzheimer Disease -- Etiology ; Amyloid Beta-Protein Precursor -- Physiology ; Extracellular Space -- Metabolism
    ISSN: 0027-8424
    E-ISSN: 10916490
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