Aβ42 Is Essential for Parenchymal and Vascular Amyloid Deposition in Mice

McGowan, Eileen; Pickford, Fiona; Kim, Jung-Su; Onstead, Luisa; Eriksen, Jason L.; Yu, Cindy; Skipper, Lisa; Murphy, Michael P.; Beard, J. David; Das, Pritam; Jansen, Karen; DeLucia, Michael W.; Lin, Weili; Dolios, Georgia; Wang, Rong; Eckman, Christopher B.; Dickson, Dennis W.; Hutton, Mike; Hardy, John; Golde, Todd E.

doi:10.1016/j.neuron.2005.06.030

Cited by 512 publications

(473 citation statements)

References 41 publications

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“…In agreement with Aβ42 having higher hydrophobicity and higher toxicity than Aβ40 in vitro and in vivo, a large number of reports also show that Aβ42 contributes to synaptic dysfunctions [31][32][33][34] . Herein, we compared the toxicity of Aβ40, Aβ42 and Aβ43.…”

Section: Neural Toxicity and Amyloid Pathology Of Aβ43mentioning

confidence: 63%

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Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, found just as frequently in patient brains, remains unresolved. We generated knockin mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygous mice exhibited embryonic lethality, indicating that the mutation involves loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevation of Aβ43 levels, impairment of short-term memory, and acceleration of Aβ pathology, accompanying pronounced accumulation of Aβ43 in plaque cores similar to the biochemical composition observed in patient brains. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aȕ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic, and abundant in vivo. 3 Alzheimer's disease, the most common form of dementia, is characterized by two pathological features in the brain, extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques consist of amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. Two major forms of Aβ exist, Aβ40 and Aβ42, with Aβ42 being more neurotoxic due to its higher hydrophobicity, which results in faster oligomerization and aggregation 1 . A number of mutations associated with early-onset familial Alzheimer's disease (FAD) have been identified in the APP, PSEN1 and PSEN2 genes, and these mutations lead to accelerated production of Aβ42 or an increase in the Aβ42/Aβ40 ratio. Together these findings indicate that Aβ42 plays an essential role in the initiation of pathogenesis. However, the possible involvement of longer Aβ species that also exist in Alzheimer's disease brains has not yet been fully investigated.Thus far, various longer Aβ species, such as Aβ43, Aβ45, Aβ48, Aβ49 and Aβ50, have been qualitatively described in Alzheimer's disease brains 2 . Similar Aβ species have also been found in transgenic mice that overexpress APP carrying FAD-linked mutations 3 . Further quantitative studies have revealed that Aβ43 is deposited more frequently than Aβ40 in both sporadic Alzheimer's disease (SAD) and FAD [4][5][6][7] .How these Aβ species with different C-terminal ends are generated from the precursor has mainly been investigated by cell biological and biochemical methods. A number of studies 8,9 demonstrated that γ/ε-cleavage by γ-secretase activity controls the fate of the C-terminal end. Aβ43, generated from Aβ49 via Aβ46, is subsequently converted to Aβ40 by γ-secretase whereas Aβ42 is independently generated from Aβ48 via Aβ45. It has also been reported that the FAD-associated I213T mutation in the PSEN1 gene increases the generation of longer Aβ species, such as Aβ43, Aβ45 a...

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Section: Neural Toxicity and Amyloid Pathology Of Aβ43mentioning

confidence: 63%

“…Previous studies have elegantly demonstrated that Aβ42 is essential for amyloid deposition in vivo 31 and that Aβ40 inhibits this deposition 32 , based on the use of Bri-Aβ fusion proteins. The difference between Aβ40 and Aβ42 lies in the carboxyl-terminal amino-acid sequence, i.e.…”

Section: Discussionmentioning

confidence: 99%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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“…After centrifugation at 4 °C at 100,000 × g for 1 h, the supernatant was collected and stored at −80 °C until assayed. Brain samples were run in triplicate on ELISA plates coated with a monoclonal anti-Aβ1-16 antibody (kindly provided by Dr. William Van Nostrand, Stony Brook University, Stony Brook, NY) and detection was by monoclonal HRP conjugated anti-Aβ1-40 (MM32-13.1.1) and anti-Aβ1-42 (MM40-21.3.1) antibodies (kindly provided by Dr. Christopher Eckman, Mayo Clinic Jacksonville, Jacksonville, CA) [9,28,37]. For standards, Aβ1-40 and Aβ1-42 (Bachem California, Inc., Torrance, CA) were used after a pretreatment with HFIP to prevent fibril formation.…”

Section: Aβ Elisamentioning

confidence: 99%

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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“…In the AD brain, intracellular accumulation of hyperphosphorylated Tau aggregates and extracellular amyloid deposits comprise the two major pathological hallmarks of the disease (1,4). A␤ aggregation has been shown to initiate from A␤1-42, a peptide normally cleaved from the amyloid precursor protein (APP) via activities of ␣-and ␥-secretases (5,6). A large body of evidence in the past decade has indicated that accumulated soluble oligomers of A␤1-42, likely the earliest or intermediate forms of A␤ deposition, are potently toxic to neurons.…”

mentioning

confidence: 99%

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Zhao

Lacor

Chen

et al. 2009

Journal of Biological Chemistry

133

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Accumulation of amyloid ␤ (A␤) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of A␤. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied A␤ oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to A␤ aggregation and subsequent synaptic loss.Abnormal protein misfolding and aggregation are common features in neurodegenerative diseases such as Alzheimer (AD), 2 Parkinson, Huntington, and prion diseases (1-3). In the AD brain, intracellular accumulation of hyperphosphorylated Tau aggregates and extracellular amyloid deposits comprise the two major pathological hallmarks of the disease (1, 4). A␤ aggregation has been shown to initiate from A␤1-42, a peptide normally cleaved from the amyloid precursor protein (APP) via activities of ␣-and ␥-secretases (5, 6). A large body of evidence in the past decade has indicated that accumulated soluble oligomers of A␤1-42, likely the earliest or intermediate forms of A␤ deposition, are potently toxic to neurons. The toxic effects of A␤ oligomers include synaptic structural deterioration (7,8) and functional deficits such as inhibition of synaptic transmission (9) and synaptic plasticity (10 -13), as well as memory loss (11,14,15). Accumulation of high levels of these oligomers may also trigger inflammatory processes and oxidative stress in the brain probably due to activation of astrocytes and microglia (16,17). Thus, to understand how a physiologically produced peptide becomes a misfolded toxin has been one of the key issues in uncovering the molecular pathogenesis of the disease.A␤ accumulation and aggregation could derive from overproduction or impaired clearance. Mutations of APP or presenilins 1 and 2, for example, are shown to cause overproduction of A␤1-42 and amyloid deposits in the brain of early onset AD (18,19). Because early onset AD accounts for less than 5% of entire AD population, APP and presenilin mutati...

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Aβ42 Is Essential for Parenchymal and Vascular Amyloid Deposition in Mice

Cited by 512 publications

References 41 publications

Potent amyloidogenicity and pathogenicity of Aβ43

Potent amyloidogenicity and pathogenicity of Aβ43

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

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

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