Decreased clearance of CNS beta-amyloid in Alzheimer's disease.

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science (Impact Factor: 31.48). 12/2010; 330(6012):1774. DOI: 10.1126/science.1197623
Source: PubMed

ABSTRACT Alzheimer's disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer's disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer's disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer's disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer's disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer's disease is characterized by an overall impairment in Aβ clearance.

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    ABSTRACT: Amyloid-β (Aβ) peptide has been implicated in the pathogenesis of Alzheimer's disease (AD). We present a nonpharmacological approach for removing Aβ and restoring memory function in a mouse model of AD in which Aβ is deposited in the brain. We used repeated scanning ultrasound (SUS) treatments of the mouse brain to remove Aβ, without the need for any additional therapeutic agent such as anti-Aβ antibody. Spinning disk confocal microscopy and high-resolution three-dimensional reconstruction revealed extensive internalization of Aβ into the lysosomes of activated microglia in mouse brains subjected to SUS, with no concomitant increase observed in the number of microglia. Plaque burden was reduced in SUS-treated AD mice compared to sham-treated animals, and cleared plaques were observed in 75% of SUS-treated mice. Treated AD mice also displayed improved performance on three memory tasks: the Y-maze, the novel object recognition test, and the active place avoidance task. Our findings suggest that repeated SUS is useful for removing Aβ in the mouse brain without causing overt damage, and should be explored further as a noninvasive method with therapeutic potential in AD. Copyright © 2015, American Association for the Advancement of Science.
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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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