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

Jiang, Ying; Mullaney, Kerry; Peterhoff, Corrinne M.; Che, Shaoli; Schmidt, Stephen D.; Boyer-Boiteau, Anne; Ginsberg, Stephen D.; Cataldo, Anne M.; Mathews, Paul M.; Nixon, Ralph A.

doi:10.1073/pnas.0908953107

Cited by 264 publications

(342 citation statements)

References 36 publications

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“…In the current study, we found that V 0 ATPase is both oxidized and polyubiquitinated (DS vs. Ctr Y and Ctr O vs. Ctr Y), and we hypothesize that these modifications decrease the V 0 -ATPase proton pump activity consistent with autophagy dysfunction. Accordingly, the Nixon group has demonstrated reduced acidification of lysosomes in AD (73), and genetic mutation of lysosomal ATPase is among the risk factors recognized to contribute to autophagy-related neurodegenerative diseases (37,52). Furthermore, disturbance of autophagosome formation coupled with hyperactivation of the mTOR pathway is observed in DS brain, before and after development of AD pathology (59).…”

Section: Discussionmentioning

confidence: 99%

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

Tramutola

Domenico

Barone

et al. 2017

Antioxidants & Redox Signaling

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Aims: Among the putative mechanisms proposed to be common factors in Down syndrome (DS) and Alzheimer's disease (AD) neuropathology, deficits in protein quality control (PQC) have emerged as a unifying mechanism of neurodegeneration. Considering that disturbance of protein degradation systems is present in DS and that oxidized/misfolded proteins require polyubiquitinylation for degradation via the ubiquitin proteasome system, this study investigated if dysregulation of protein polyubiquitinylation is associated with AD neurodegeneration in DS. Results: Postmortem brains from DS cases before and after development of AD neuropathology and age-matched controls were analyzed. By selectively isolating polyubiquitinated proteins, we were able to identify specific proteins with an altered pattern of polyubiquitinylation as a function of age. Interestingly, we found that oxidation is coupled with polyubiquitinylation for most proteins mainly involved in PQC and energy metabolism. Innovation: This is the first study showing alteration of the polyubiquitinylation profile as a function of aging in DS brain compared with healthy controls. Understanding the onset of the altered ubiquitome profile in DS brain may contribute to identification of key molecular regulators of age-associated cognitive decline. Conclusions: Disturbance of the polyubiquitinylation machinery may be a key feature of aging and neurodegeneration. In DS, age-associated deficits of the proteolytic system may further exacerbate the accumulation of oxidized/misfolded/polyubiquitinated proteins, which is not efficiently degraded and may become harmful to neurons and contribute to AD neuropathology. Antioxid. Redox Signal. 26,[280][281][282][283][284][285][286][287][288][289][290][291][292][293][294][295][296][297][298]

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Section: Discussionmentioning

confidence: 99%

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

Tramutola

Domenico

Barone

et al. 2017

Antioxidants & Redox Signaling

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“…Moreover, an extra copy of APP is sufficient to cause endosomal enlargement and intracellular trafficking defects 141,142 via an Aβ-independent mechanism 143 . Enlargement of endosomes in trisomic neurons may cause axonal trafficking defects that contribute to neuronal degeneration 141 .…”

Section: Disruption Of Secretory and Endosomal Systemsmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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“…Conversely, βAPP expression is decreased in somas of neurons proximal to Aβ plaques in normal aging and in AD, and such βAPP seems to be redistributed from the neuron soma to dystrophic neurites (16), swollen stretches of axons, or dendrites containing mainly stalled vesicular traffic from the endocytic and autophagic pathways (17). These findings may be related to the accelerated endocytic activity and downstream dysfunction observed early on in DS and AD described in Jiang et al (1) in this issue of PNAS. The revelation that excess βAPP and its mediating factor βCTF, rather than Aβ, are the culprits in endocytic dysfunction in DS, together with the findings of other investigators regarding a role for overexpression of neuronal βAPP as a result of AD risk-conferring conditions, not only pinpoints βAPP-related targets for development of therapeutic interventions to prevent or forestall pathogenesis, but as importantly, it highlights the possibility that excess βAPP and its mediating factors such as βCTF and sAPP are more involved as initiators of pathogenesis than has previously been recognized.…”

Section: βApp Endosomes and Neurodegenerationmentioning

confidence: 70%

“…T he article by Jiang et al (1) in this issue of PNAS goes a good way toward explaining early consequences of elevated expression of β-amyloid precursor protein (βAPP) and its β-secretase-cleaved carboxyl-terminal fragment (βCTF) in the endocytic dysfunction present early on in Alzheimer's disease (AD) and Down's syndrome (DS or trisomy 21). The authors pose a straightforward question: is duplication of the βAPP gene in DS sufficient to precipitate endocytic dysfunction?…”

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confidence: 99%

Excess βCTF, not Aβ: The culprit in Alzheimer-related endocytic dysfunction

Griffin

2010

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

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T he article by Jiang et al. (1) in this issue of PNAS goes a good way toward explaining early consequences of elevated expression of β-amyloid precursor protein (βAPP) and its β-secretase-cleaved carboxyl-terminal fragment (βCTF) in the endocytic dysfunction present early on in Alzheimer's disease (AD) and Down's syndrome (DS or trisomy 21). The authors pose a straightforward question: is duplication of the βAPP gene in DS sufficient to precipitate endocytic dysfunction? Using an elegantly simple approach in fibroblasts from individuals with trisomy 21 (3N), the authors show that either suppressing the expression of the extra βAPP gene by shRNA or decreasing the production of βCTF by inhibiting the βAPP β-secretase, BACE-1, reverses the dramatic pathologic changes in endocytic morphology (endosome enlargement) and function (accelerated uptake) noted in trisomy 21 or in βAPP overexpressing 2N fibroblasts. Their finding that overexpression of a mutated form of βAPP lacking the BACE-1 cleavage site in 2N fibroblasts did not produce the endocytic dysfunction showed conclusively that the mediating factor in the βAPP-related induction of endocytic dysfunction is βCTF. However, just to be sure that the endocytic anomalies necessitated only βCTF overexpression, they also showed that similar endocytic dysfunction is elicited when β amyloid (Aβ) production is reduced and βAPP and βCTF production is increased by γ-secretase inhibition in 2N cells. Findings such as these signify an important change, perhaps a sea change, in our understanding of the potential pathogenic role of overexpressing βAPP, relative to that of Aβ, at least in the arena of early endocytic dysfunction and its downstream consequences in AD and DS. Although Aβ continues to be the principal focus of investigations into both the causes and consequences of AD, these and other findings are beginning to highlight the fundamental importance of Aβ-independent pathogenic roles of βAPP and its various proteolytic products in AD.βAPP Rises in Alzheimer-Related Neural Injury and Neuroinflammation The βAPP-induced endosomal pathologies noted by Jiang et al.(1) may be related to and likely accompany other early events that occur before the development of the neuritic Aβ plaques in DS. For example, glial activation with overexpression of the proinflammatory cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B (2) accompanies the dramatic overexpression of βAPP in brains of DS fetuses (3).As further evidence of a seminal role of βAPP and its mediating products in sporadic AD, neuronal overexpression of βAPP with activation of glia and overexpression of these cytokines is an earlyThe mediating factor in the βAPP-related induction of endocytic dysfunction is βCTF.and prominent response in conditions that increase risk for development of AD, including traumatic brain injury (TBI), excitotoxicity as in epilepsy, viral infections as in AIDS, and more subtle insults such as aging (4). In vitro simulation of stress-induced increases in neuronal βAPP are accompa...

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

Cited by 264 publications

References 36 publications

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Excess βCTF, not Aβ: The culprit in Alzheimer-related endocytic dysfunction

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