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: 4). 03/2010; 2(8):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.

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Available from: Thomas A Bayer
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    • "Intraneuronal Aβ accumulation has been observed in human AD brains, in several rodent models of AD (Gouras et al., 2000; D'Andrea et al., 2001; Busciglio et al., 2002; Mori et al., 2002; Oddo et al., 2003; Cataldo et al., 2004; Echeverria et al., 2004; Cruz et al., 2006; Oakley et al., 2006; LaFerla et al., 2007), and, more recently, also in brains of aged mouse lemur primates (Roy et al., 2014). Within neurons, Aβ accumulates on the outer membrane of multivesicular bodies, both in somas and neurites (Takahashi et al., 2002; Casas et al., 2004; Cataldo et al., 2004), and is associated with early pathological alterations in dendrites, axonal terminals and synapses (Takahashi et al., 2004; Bayer and Wirths, 2010; Gouras et al., 2010). Clearance of intraneuronal Aβ by immunotherapy was shown to protect synapses and improve memory in in vitro and in vivo models of AD (Billings et al., 2005; Tampellini et al., 2007). "

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    • "Intraneuronal Aβ accumulation has been observed in human AD brains, in several rodent models of AD (Gouras et al., 2000; D'Andrea et al., 2001; Busciglio et al., 2002; Mori et al., 2002; Oddo et al., 2003; Cataldo et al., 2004; Echeverria et al., 2004; Cruz et al., 2006; Oakley et al., 2006; LaFerla et al., 2007), and, more recently, also in brains of aged mouse lemur primates (Roy et al., 2014). Within neurons, Aβ accumulates on the outer membrane of multivesicular bodies, both in somas and neurites (Takahashi et al., 2002; Casas et al., 2004; Cataldo et al., 2004), and is associated with early pathological alterations in dendrites, axonal terminals and synapses (Takahashi et al., 2004; Bayer and Wirths, 2010; Gouras et al., 2010). Clearance of intraneuronal Aβ by immunotherapy was shown to protect synapses and improve memory in in vitro and in vivo models of AD (Billings et al., 2005; Tampellini et al., 2007). "
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    ABSTRACT: Synapses have been known for many years to be the crucial target of pathology in different forms of dementia, in particular Alzheimer's disease (AD). Synapses and their appropriate activation or inhibition are fundamental for the proper brain function. Alterations in synaptic/neuronal activity and brain metabolism are considered among the earliest symptoms linked to the progression of AD, and lead to a central question in AD research: what is the role played by synaptic activity in AD pathogenesis? Intriguingly, in the last decade, important studies demonstrated that the state of activation of synapses affects the homeostasis of beta-amyloid (Aβ) and tau, both of which aggregate and accumulate during AD, and are involved in neuronal dysfunction. In this review we aim to summarize the up-to-date data linking synaptic/neuronal activity with Aβ and tau; moreover, we also intend to provide a critical overview on brain activity alterations in AD, and their role in the disease's pathophysiology.
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    • "In contrast, α-secretase cleaves APP within the Aβ domain, precluding the generation of Aβ in normal APP metabolism. While extracellular Aβ aggregation has long been considered as a key culprit in AD onset, intracellular Aβ accumulation is detected in neurons prior to the appearance of extracellular deposits (Wirths et al., 2001; Youmans et al., 2012) and is associated with cytotoxicity, dysfunction of organelles, and neurodegeneration (Bayer and Wirths, 2010). While the rare autosomal dominant familial AD is mostly due to overproduction of Aβ (O'Brien and Wong, 2011) or enhancing Aβ protofibril formation, far more common is the late-onset sporadic AD (sAD), thought to be caused, in part, by decreased clearance of the Aβ peptide from the CNS (Dorfman et al., 2010; Mawuenyega et al., 2010; Silverberg et al., 2010a). "
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    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.
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