Sequence of Deposition of Heterogeneous Amyloid β-Peptides and APO E in Down Syndrome: Implications for Initial Events in Amyloid Plaque Formation

Lemere, Cynthia A.; Blusztajn, J. K.; Yamaguchi, Hideyo; Wısnıewskı, Thomas; Saido, Takaomi C.; Selkoe, Dennis J.

doi:10.1006/nbdi.1996.0003

Cited by 524 publications

(411 citation statements)

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“…Increased Aβ in the insoluble pools occurs at approximately the same age as a shift in APP processing to favor the production of amyloidogenic fragments. Overall, Aβ42 in the insoluble pool was higher than Aβ40, which is consistent with immunohistochemical studies of Aβ in the plaques of DS brain [30].…”

Section: Discussionsupporting

confidence: 88%

“…We did not observe significant differences in the levels of insoluble Aβ in younger DS cases as compared to controls suggesting that insoluble Aβ reflects either an aging or a disease process. However, our ELISA capture antibody will not detect N-terminally truncated species of Aβ that have been previously reported to also rise with age in DS [30] and thus our measures may be conservative.…”

Section: Discussionmentioning

confidence: 99%

“…However, Aβ within diffuse plaques and compact plaques has also been observed occasionally in the temporal cortex of individuals under 40 years (i.e. in childhood, teens and in early adulthood) [30,31]. These reports suggest that APP processing may lead to the production of nonamyloidogenic fragments at younger ages and shift to favor production of Aβ in later years.…”

Section: Introductionmentioning

confidence: 94%

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Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

104

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Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alphasecretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Aβ) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Aβ degradation and clearance.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

104

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“…This hypothesis fails to explain several important pathological and clinical characteristics of AD, raising the possibility that a species other than amyloid fibrils could be the toxic species (Goldberg & Lansbury, 2000). First, there is no correlation between the amounts of fibrillar Ab deposits at autopsy and the clinical severity of AD (Lemere et al 1996 ;Terry et al 1991). Such a correlation does exist between ' soluble Ab' (monomers plus protofibrils) in the brain and early cognitive dysfunction (Lue et al 1999 ;McLean et al 1999 ;Naslund et al 2000).…”

Section: In Vitro Fibril Formation Involves Transient Population Of Omentioning

confidence: 99%

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

Lashuel

Lansbury

2006

Quart. Rev. Biophys.

372

368

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Abstract. Protein fibrillization is implicated in the pathogenesis of most, if not all, ageassociated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ' amyloid pore'. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.

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“…Furthermore, patients with Down syndrome develop AD early in life and show overproduction of Aβ and plaque deposition in the brain before tangles and other AD lesions. 55 Based on these observations, the accumulation of Aβ in the brain was described by Hardy and Allsop as the key event in the pathogenesis of AD more than 20 years ago. 56 The so-called "amyloid cascade hypothesis" suggested that the accumulation and aggregation of Aβ, specifically Aβ 42 , would trigger further pathological events such as formation of NFTs, disruption of synaptic connections with decreased neurotransmitters release, microglial and astrocytes activation in a chronic inflammation response, initiates neuronal loss and ultimately leads to dementia.…”

Section: ■ Amyloid Cascade Hypothesismentioning

confidence: 96%

Alzheimer’s Disease: Pathophysiology and Applications of Magnetic Nanoparticles as MRI Theranostic Agents

Amiri

Saeidi²,

Borhani³

et al. 2013

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is the most common form of dementia. During the recent decade, nanotechnology has been widely considered, as a promising tool, for theranosis (diagnosis and therapy) of AD. Here we first discuss pathophysiology and characteristics of AD with a focus on the amyloid cascade hypothesis. Then magnetic nanoparticles (MNPs) and recent works on their applications in AD, focusing on the superparamagnetic iron oxide nanoparticles (SPIONs), are reviewed. Furthermore, the amyloid−nanoparticle interaction is highlighted, with the scope to be highly considered by the scientists aiming for diagnostics and/or treatment of AD employing nanoparticles. Furthermore, recent findings on the "ignored" parameters (e.g., effect of protein "corona" at the surface of nanoparticles on amyloid-β (Aβ) fibrillation process) are discussed. KEYWORDS: Magnetic resonance imaging, SPION, amyloid-β, nanomedicine, nanotechnology A lzheimer's disease (AD) is named after Alois Alzheimer, who described the first case in a 55 year old female patient (i.e., Auguste Deter) in 1906. The description of Auguste's pathology was featured by lifelong deteriorating memory, speaking, physical, and social abilities. After her death, the autopsy revealed uniform brain atrophy, atherosclerosis changes in larger cerebral vessels, neuronal loss, and numerous small foci perceivable even without staining distributed over the entire cortex. It took over 70 years to reveal that those foci consist of aggregates of extracellular loads of small peptides called amyloid-β (Aβ), that are considered today one of the hallmarks of the disease. 1 AD is characterized by progressive deterioration of cognitive function, most commonly of memory, that increasingly interferes with patients' daily activities leading to loss of independency (for details, see http://www.alz.org/downloads/ facts_figures_2012.pdf). To date, no precise treatments have been clinically proven to avoid or prevent the progression of AD. Several different pharmacological agents can only ameliorate or provide temporary alleviation of the symptoms. 2 In this review, we introduce clinical aspects and characteristics of AD with a focus on the amyloid cascade hypothesis. Magnetic nanoparticles (MNPs), as promising theranosis tools, are introduced, and recent reports on the potential applications of superparamagnetic iron oxide nanoparticles (SPIONs) in AD are summarized. It is worthwhile to note that the SPIONs are known as promising theranosis candidates for AD, due to their biocompatibility, unique magnetic properties and multifunctional application capability. 3,4 The amyloid−nanoparticle interaction is highlighted, with the scope to be highly considered by the scientific community aiming for diagnostics and/or treatment of AD employing nanoparticles. Moreover, recent findings on the "ignored" parameters (e.g., the effect of protein "corona" at the surface of nanoparticles on Aβ fibrillation process) are discussed.

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Sequence of Deposition of Heterogeneous Amyloid β-Peptides and APO E in Down Syndrome: Implications for Initial Events in Amyloid Plaque Formation

Cited by 524 publications

References 0 publications

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

Alzheimer’s Disease: Pathophysiology and Applications of Magnetic Nanoparticles as MRI Theranostic Agents

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