Article

Intracellular Accumulation of Amyloid-Beta – A Predictor for Synaptic Dysfunction and Neuron Loss in Alzheimer's Disease

Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department of Psychiatry, University of Göttingen Göttingen, Germany.
Frontiers in Aging Neuroscience (Impact Factor: 2.84). 03/2010; 2:8. DOI: 10.3389/fnagi.2010.00008
Source: PubMed

ABSTRACT Despite of long-standing evidence that beta-amyloid (Abeta) peptides have detrimental effects on synaptic function, the relationship between Abeta, synaptic and neuron loss is largely unclear. During the last years there is growing evidence that early intraneuronal accumulation of Abeta peptides is one of the key events leading to synaptic and neuronal dysfunction. Many studies have been carried out using transgenic mouse models of Alzheimer's disease (AD) which have been proven to be valuable model systems in modern AD research. The present review discusses the impact of intraneuronal Abeta accumulation on synaptic impairment and neuron loss and provides an overview of currently available AD mouse models showing these pathological alterations.

Full-text

Available from: Thomas A Bayer, Jun 02, 2015
0 Followers
 · 
101 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently a number of aggregation disease polypeptides have been shown to spread from cell to cell thereby displaying prionoid behaviour. Studying aggregate internalisation however is often hampered by the complex kinetics of the aggregation process resulting in the concomitant uptake of aggregates of different sizes by competing mechanisms, which makes it difficult to isolate pathway-specific responses to aggregates. We designed synthetic aggregating peptides bearing different aggregation propensities with the aim of producing modes of uptake that are sufficiently distinct to differentially analyse the cellular response to internalization. We found that small acidic aggregates (≤500 nm diameter) were taken up by non-specific endocytosis as part of the fluid phase and travelled through the endosomal compartment to lysosomes. By contrast, basic bigger aggregates (>1 μm) were taken up through a mechanism dependent of cytoskeletal reorganization and membrane remodelling with the morphological hallmarks of phagocytosis. Importantly, the properties of these aggregates not only determined the mechanism of internalization but also the involvement of the proteostatic machinery (the assembly of interconnected networks that control the biogenesis, folding, trafficking and degradation of proteins) in the process: while the internalization of small acidic aggregates is HSF1 independent, the uptake of larger basic aggregates was HSF1 dependent requiring Hsp70. Our results show that the biophysical properties of aggregates determine both their mechanism of internalisation and proteostatic response. It remains to be seen whether these differences in cellular response contribute to the particular role of specific aggregated proteins in disease.
    Journal of Biological Chemistry 11/2014; 290(1). DOI:10.1074/jbc.M114.586636 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Key neuropathological hallmarks of Alzheimer's disease (AD) are elevated levels of amyloid β-peptide (Aβ) species generated via amyloid precursor protein (APP) endoproteolysis and cleavage by the rate-limiting β-site enzyme 1 (BACE1). Because rodents do not develop amyloid pathologies, we here investigated whether AD-like endophenotypes can be created in mice by expression of human bace1. To avoid pitfalls of existing models, we introduced hbace1 via knock-in under the control of the CaMKII α promoter into the safe HPRT locus. We report amyloidogenic processing of murine APP in the hBACE1 mice (termed PLB4), resulting in the formation of toxic APP metabolites that accumulate intra- and extraneuronally in hippocampus and cortex. Pronounced accumulation of Aβ*56 and Aβ hexamers in the absence of plaque deposition was detected in brain tissue from symptomatic PLB4 mice. Heightened levels of inflammation (gliosis) also appeared in several AD-related brain regions (dentate gyrus, hippocampal area CA1, piriform and parietal cortices) at 6 and 12 months of age. Behaviorally, deficits in habituation to a novel environment and semantic-like memory (social transmission of food preference) were detected from 3 to 4 months of age. Impairments in spatial learning strategies in long-term reference (water maze) and working memory (Y-maze) tasks presented at 6 months, and were distinct from reductions in locomotor activity and anxiety. Overall, our data indicate for the first time that targeted, subtle forebrain-specific expression through single gene knock-in of hBACE1 is sufficient to generate AD-relevant cognitive impairments amid corresponding histopathologies, confirming human BACE as the key parameter in amyloid pathogenesis.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2014; 34(32):10710-28. DOI:10.1523/JNEUROSCI.0433-14.2014 · 6.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Ab) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer’s disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: b-amyloid (Ab) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Ab in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Ab42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Ab transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Ab burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Ab) and diminished secretion of TTR (less neuroprotection against cortical Ab toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD.
    Frontiers in Cellular Neuroscience 02/2015; 9(17). DOI:10.3389/fncel.2015.00017 · 4.18 Impact Factor