Influence of the amyloid precursor protein locus on dementia in Down syndrome

Margallo-Lana, Marisa; Morris, Christopher M.; Gibson, A. H.; Tan, A.; Kay, D. W. K.; Tyrer, Stephen; Moore, Brian P.; Ballard, Clive

doi:10.1212/01.wnl.0000129275.13169.be

Cited by 38 publications

(35 citation statements)

References 20 publications

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“…App promoter polymorphisms that increase APP expression are also associated with early-onset AD (Athan et al 2002). These findings support a longstanding hypothesis that the App gene on the trisomic copy of human chromosome 21 (HSA21) in Down syndrome (DS) is principally responsible for the invariant early development of AD in DS individuals (Margallo-Lana et al 2004). In DS, the extra copy of App causes endocytic up-regulation and endosome pathology similar to that seen at the earliest stages of sporadic AD, but beginning even earlier.…”

Section: Ad Genetics Implicates the Lysosomal Network In Pathogenesissupporting

confidence: 80%

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

Ihara¹,

Morishima-Kawashima²,

Nixon³

2012

Cold Spring Harbor Perspectives in Medicine

153

126

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As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles-a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin-proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal-lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target.

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Section: Ad Genetics Implicates the Lysosomal Network In Pathogenesissupporting

confidence: 80%

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

Ihara¹,

Morishima-Kawashima²,

Nixon³

2012

Cold Spring Harbor Perspectives in Medicine

153

126

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“…An additional copy of the App gene (duplication) is sufficient to cause early-onset autosomal dominant AD with cerebral amyloid angiopathy (CAA) (5,6). These findings reinforce a longstanding hypothesis that the additional App gene found on the trisomic copy of human chromosome 21 (HSA21) in Down syndrome (DS) plays a critical role in the invariant early development of AD in DS individuals (7).…”

mentioning

confidence: 53%

Alzheimer’s-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition

Jiang

Mullaney

Peterhoff

et al. 2009

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

263

317

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An additional copy of the β-amyloid precursor protein (APP) gene causes early-onset Alzheimer’s disease (AD) in trisomy 21 (DS). Endosome dysfunction develops very early in DS and AD and has been implicated in the mechanism of neurodegeneration. Here, we show that morphological and functional endocytic abnormalities in fibroblasts from individuals with DS are reversed by lowering the expression of APP or β-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs. By contrast, endosomal pathology can be induced in normal disomic (2N) fibroblasts by overexpressing APP or the C-terminal APP fragment generated by BACE-1 (βCTF), all of which elevate the levels of βCTFs. Expression of a mutant form of APP that cannot undergo β-cleavage had no effect on endosomes. Pharmacological inhibition of APP γ-secretase, which markedly reduced Aβ production but raised βCTF levels, also induced AD-like endosome dysfunction in 2N fibroblasts and worsened this pathology in DS fibroblasts. These findings strongly implicate APP and the βCTF of APP, and exclude Aβ and the αCTF, as the cause of endocytic pathway dysfunction in DS and AD, underscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics.

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“…Autophagy-related 'rimmed' vacuoles containing APP, A␤, BACE and presenilin (Askanas and Engel, 1998; Askanas et al, 1998) also accumulate in inclusion-body myositis, a rare instance in which ␤-amyloid is deposited outside the nervous system . Upregulated endocytosis at early stages of AD also increases the delivery of APP-rich compartments to the autophagic pathway and is accelerated by App triplication, which causes early-onset AD in families and in Down syndrome (Margallo-Lana et al, 2004;Prasher et al, 1998), and by inheritance of the E4 isoform of the apolipoprotein E gene (apo E) (Cataldo et al, 1997), the strongest genetic risk factor for late-onset AD.…”

Section: Autophagy Dysfunction In Alzheimer Diseasementioning

confidence: 99%

Autophagy, amyloidogenesis and Alzheimer disease

Nixon

2007

Journal of Cell Science

655

528

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APP biology in briefAPP is a member of a family of conserved type 1 membrane proteins, which includes in mammals APP-like protein (APLP) 1 and APLP2 (Coulson et al., 2000;Senechal et al., 2006). Although its function remains uncertain, putative physiological roles in trafficking, neurotrophic signaling, cell adhesion and cell signaling have been proposed (Reinhard et al., 2005;Zheng and Koo, 2006;Hoareau et al., 2006).After APP is synthesized, the mature glycosylated form of APP in the trans-Golgi network (TGN) is delivered to the plasma membrane, where it is fairly rapidly turned over by either of two mechanisms (Fig. 3). An aspartyl protease at the cell surface, tumor necrosis factor ␣ converting enzyme Autophagy is the sole pathway for organelle turnover in cells and is a vital pathway for degrading normal and aggregated proteins, particularly under stress or injury conditions. Recent evidence has shown that the amyloid ␤ peptide is generated from amyloid ␤ precursor protein (APP) during autophagic turnover of APP-rich organelles supplied by both autophagy and endocytosis. A␤ generated during normal autophagy is subsequently degraded by lysosomes. Within neurons, autophagosomes and endosomes actively form in synapses and along neuritic processes but efficient clearance of these compartments requires their retrograde transport towards the neuronal cell body, where lysosomes are most concentrated. In Alzheimer disease, the maturation of autophagolysosomes and their retrograde transport are impeded, which leads to a massive accumulation of 'autophagy intermediates' (autophagic vacuoles) within large swellings along dystrophic and degenerating neurites. The combination of increased autophagy induction and defective clearance of A␤-generating autophagic vacuoles creates conditions favorable for A␤ accumulation in Alzheimer disease. Journal of Cell Science4083 Autophagy, amyloidogenesis and AD (TACE) or a distintegrin and metalloproteinase 10 (ADAM10) (Lopez-Perez et al., 2001;Buxbaum et al., 1998), also referred to as ␣-secretase, can mediate ␣-cleavage of APP within its lumenal/extracellular domain to generate a large soluble Nterminal fragment (sAPP␣), which is released from the cell, and a C-terminal fragment (CTF) that remains membrane associated. Alternatively, cell surface APP is internalized within early endosomes, where cleavage at a more distal site along the lumenal/extracellular domain by ␤-site-APPcleaving enzyme (BACE, ␤-secretase) releases a soluble APP fragment (sAPP ␤) and generates a membrane-associated 99-residue CTF (␤CTF) that contains the whole A␤ peptide. A transmembrane aspartyl protease that has optimal activity at low pH distributes predominantly to endosomes (Vassar et al., 1999;Capell et al., 2000;Walter et al., 2001), where ␤CTF has been shown to be generated (Grbovic, 2003;Mathews et al., 2002), although additional BACE is found in the TGN (von Arnim et al., 2006) (Fig. 3).A␤ is generated from ␤CTF by an intramembrane ␥-cleavage that yields predominantly a 40-mer peptide (A␤40) and s...

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Influence of the amyloid precursor protein locus on dementia in Down syndrome

Abstract: APP is an important locus predicting the age at onset of dementia in people with Down syndrome.

Cited by 38 publications

References 20 publications

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

Alzheimer’s-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition

Autophagy, amyloidogenesis and Alzheimer disease

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