Amyloid <i>β</i> 1-42 deposits do not lead to Alzheimer's neuritic plaques in aged dogs

Wısnıewskı, Thomas; Łałowski, Maciej; Bobik, Marketta; Russell, Michael J.; Strosznajder, Joanna B.; Frangione, Blas

doi:10.1042/bj3130575

Cited by 59 publications

(30 citation statements)

References 43 publications

(58 reference statements)

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“…Early MD simulations of amyloidogenic peptides (5,25) consisting of U-shaped β-strandturn-β-strand peptides in the bilayer predicted ion-permeable channels formed by loosely attached mobile subunits with morphologies and dimensions similar to the AFM-images of amyloid channels (7,8). U-shaped motifs, first predicted by modeling of Aβ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (26), appear as a general feature of amyloid organization, suggesting that other U-shaped amyloid organizations may also form dynamic ion channels in the fluidic membrane (8). Because N9 and p3 have membrane-spanning segments, we modeled their 3D structures in the bilayer using the previous successful protocol (5,25).…”

Section: Resultsmentioning

confidence: 99%

“…Because of their nonamyloidogenic nature, these peptides are assumed to be nonpathogenic and these pathways are even being targeted for AD therapeutics. Significantly, p3 peptides are present in AD amyloid plaques (17)(18)(19)(20), are the main constituent of cerebellar preamyloid lesions in Down syndrome (21) and induce neuronal toxicity (22-24). However, their biophysical properties, mechanism of toxicity, and pathological significance in AD and Down syndrome remain unclear.…”

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confidence: 99%

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Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Jang

Arce

Ramachandran

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

214

344

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Full-length amyloid beta peptides (Aβ 1-40/42 ) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. However, recent transgenic animal models cast doubt on their direct role in AD pathology. Nonamyloidogenic truncated amyloid-beta fragments and Aβ ) are also found in amyloid plaques of AD and in the preamyloid lesions of Down syndrome, a model system for early-onset AD study. Very little is known about the structure and activity of these smaller peptides, although they could be the primary AD and Down syndrome pathological agents. Using complementary techniques of molecular dynamics simulations, atomic force microscopy, channel conductance measurements, calcium imaging, neuritic degeneration, and cell death assays, we show that nonamyloidogenic Aβ 9-42 and Aβ 17-42 peptides form ion channels with loosely attached subunits and elicit single-channel conductances. The subunits appear mobile, suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in amyloid precursor protein-deficient cells. The channel mediated calcium uptake induces neurite degeneration in human cortical neurons. Channel conductance, calcium uptake, and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus, truncated Aβ fragments could account for undefined roles played by full length Aβs and provide a unique mechanism of AD and Down syndrome pathologies. The toxicity of nonamyloidogenic peptides via an ion channel mechanism necessitates a reevaluation of the current therapeutic approaches targeting the nonamyloidogenic pathway as avenue for AD treatment.atomic force microscopy | molecular dynamics | cell calcium imaging | neurite degeneration and cell death assays | single-channel conductance A myloid-beta peptides (Aβ 1-40/42 ) produced by β-and γ-secretase processing of amyloid precursor protein (APP) in the amyloidogenic pathway are involved in Alzheimer's disease (AD) pathology. Aβ 1-40/42 peptides form β-sheet-rich ordered aggregates and soluble oligomers. Small oligomers are emerging as the predominant toxic species (1-3); the toxicity is believed to be a result of the loss of ionic homeostasis, presumably via ion channels formed in cellular membranes (4, 5). EM images of Aβ oligomers show doughnut-like morphologies (6). Atomic force microscopic (AFM) images of Aβ peptides reconstituted in lipid bilayers show heteromeric (rectangular to hexagonal) ion channel-like structures with a ∼2.0-nm central pore and 8-to 12-nm outer diameters (7,8). Electrophysiological studies show heterodisperse cationselective single-channel conductances (7)(8)(9)(10)(11)(12)(13)(14) that are consistent with features of other amyloid ion channels (6-8).On the other hand, when APP is cleaved by γ-and α-secretases, it forms the nonamyloidogenic pathway generating ∼2.6-kDa fragments (Aβ 17-40/42 ) known as the p3 peptides (15). Cleavage by γ and BACE between Tyr10 and Glu11 generates another...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Jang

Arce

Ramachandran

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

214

344

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“…Limited published studies indicate that A␤-related parenchymal preamyloid lesions are enriched in species ending at position 42. The ␣-secretase fragment A␤- , in particular, was previously identified as the main component of preamyloid lesions in AD (34), Down syndrome (35), and aged dogs (36), A␤-(1-42) and A␤-(4 -42) being minor components in the last two cases. In FDD extracts, A␤-(17-42) was not detected, and although it could be argued that the present extraction conditions were milder than those previously reported (2% SDS versus 15% SDS), thereby precluding the retrieval of A␤-(17-42), this fragment was also undetected in the subsequent formic acid extracts.…”

Section: Discussionmentioning

confidence: 99%

Familial Danish Dementia

Tomidokoro

Lashley²,

Rostagno

et al. 2005

Journal of Biological Chemistry

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Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in the BRI2 gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules (Danish amyloid (ADan) and ␤-amyloid (A␤)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical analysis of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with A␤-(1-42) and A␤-(4-42) in ϳ1:1 mixture. The post-translational modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally modified (pyroglutamate), whereas A␤ was mainly A␤-(4-42). In all cases, the presence of A␤-(X-40) was negligible, a surprising finding in view of the prevalence of A␤40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and A␤ molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. Theabsenceofcompactplaquesinthepresenceofextensiveneurofibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.

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“…6 Vascular Ab typically includes the shorter 1-40 species, which is identical in dogs and humans. 208 As with human brain aging and AD, there is increasing recognition that CAA can be a contributor to clinical signs of cognitive dysfunction in Figure 17. Corpora amylacea in the neuropil of diencephalon, in an aged dog (14 years old) with no neurological signs.…”

Section: Vascular Lesionsmentioning

confidence: 99%

Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases

et al. 2016

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According to the WHO, the proportion of people over 60 years is increasing and expected to reach 22% of total world's population in 2050. In parallel, recent animal demographic studies have shown that the life expectancy of pet dogs and cats is increasing. Brain aging is associated not only with molecular and morphological changes but also leads to different degrees of behavioral and cognitive dysfunction. Common age-related brain lesions in humans include brain atrophy, neuronal loss, amyloid plaques, cerebrovascular amyloid angiopathy, vascular mineralization, neurofibrillary tangles, meningeal osseous metaplasia, and accumulation of lipofuscin. In aging humans, the most common neurodegenerative disorder is Alzheimer's disease (AD), which progressively impairs cognition, behavior, and quality of life. Pathologic changes comparable to the lesions of AD are described in several other animal species, although their clinical significance and effect on cognitive function are poorly documented. This review describes the commonly reported age-associated neurologic lesions in domestic and laboratory animals and the relationship of these lesions to cognitive dysfunction. Also described are the comparative interspecies similarities and differences to AD and other human neurodegenerative diseases including Parkinson's disease and progressive supranuclear palsy, and the spontaneous and transgenic animal models of these diseases.

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Amyloid β 1-42 deposits do not lead to Alzheimer's neuritic plaques in aged dogs

Cited by 59 publications

References 43 publications

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Familial Danish Dementia

Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases

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