Pathophysiological Roles of Amyloidogenic Carboxy-Terminal Fragments of the β-Amyloid Precursor Protein in Alzheimer’s Disease

Chang, Keun-A; Suh, Yoo‐Hun

doi:10.1254/jphs.cr0050014

Cited by 64 publications

(47 citation statements)

References 99 publications

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“…S2), confirming that LXR agonists do not alter APP abundance. Previous studies have demonstrated that carboxyl-terminal fragments (CTF) of APP impair calcium homeostasis and learning and memory and are an important toxic component in the neuropathy of AD (38). Intriguingly, we observed a trend toward increased CTF␣ and CTF␤ levels only in the hippocampus of mice treated with 33 mg/kg/day of GW3965 (supplemental Fig.…”

Section: Gw3965 Increases Abca1 and Apoe Protein Levels In A Dose-depmentioning

confidence: 49%

ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

Donkin

Stukas

Hirsch‐Reinshagen

et al. 2010

Journal of Biological Chemistry

175

148

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The cholesterol transpoter ATP-binding cassette transporter A1 (ABCA1) moves lipids onto apolipoproteins including apolipoprotein E (apoE), which is the major cholesterol carrier in the brain and an established genetic risk factor for late-onset Alzheimer disease (AD). In amyloid mouse models of AD, ABCA1 deficiency exacerbates amyloidogenesis, whereas ABCA1 overexpression ameliorates amyloid load, suggesting a role for ABCA1 in A␤ metabolism. Agonists of liver X receptors (LXR), including GW3965, induce transcription of several genes including ABCA1 and apoE, and reduce A␤ levels and improve cognition in AD mice. However, the specific role of ABCA1 in mediating beneficial responses to LXR agonists in AD mice is unknown. We evaluated behavioral and neuropathogical outcomes in GW3965-treated female APP/PS1 mice with and without ABCA1. Treatment of APP/PS1 mice with GW3965 increased ABCA1 and apoE protein levels. ABCA1 was required to observe significantly elevated apoE levels in brain tissue and cerebrospinal fluid upon therapeutic (33 mg/kg/day) GW3965 treatment. At 33 mg/kg/day, GW3965 was also associated with a trend toward redistribution of A␤ to the carbonate-soluble pool independent of ABCA1. APP/PS1 mice treated with either 2.5 or 33 mg/kg/day of GW3965 showed a clear trend toward reduced amyloid burden in hippocampus and whole brain, whereas APP/ PS1-treated mice lacking ABCA1 failed to display reduced amyloid load in the whole brain and showed trends toward increased hippocampal amyloid. Treatment of APP/PS1 mice with either dose of GW3965 completely restored novel object recognition memory to wild-type levels, which required ABCA1. These results suggest that ABCA1 contributes to several beneficial effects of the LXR agonist GW3965 in APP/PS1 mice.Lipid metabolism is increasingly recognized to play a key role in the pathogenesis of Alzheimer disease (AD), 4 which is the leading cause of dementia in the elderly (1). AD is characterized by the presence of two neuropathological hallmarks including extracellular amyloid plaques that consist mainly of aggregated A␤ peptides and intracellular neurofibrillary tangles consisting of hyperphosphorylated Tau protein (2). Although the pathogenesis of AD is not completely understood, a leading hypothesis is that aberrant metabolism of A␤ peptides, which are derived by proteolytic cleavage from amyloid precursor protein (APP), triggers many of the toxic events in AD and eventually leads to both Tau and amyloid pathologies (3). Less than 5% of AD patients exhibit disease onset in their 40s and 50s due to genetic mutations that lead to increased production of A␤ peptides, particularly of the most detrimental A␤42 species (4). The cause of AD in more than 95% of subjects that typically develop AD in late life is unknown. As production of A␤ is generally not altered in these patients, age-related defects in A␤ degradation and clearance is emerging as a leading hypothesis for development of AD in the majority of patients (5).In mice, apoE exists in only one allelic state, ...

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Section: Gw3965 Increases Abca1 and Apoe Protein Levels In A Dose-depmentioning

confidence: 49%

ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

Donkin

Stukas

Hirsch‐Reinshagen

et al. 2010

Journal of Biological Chemistry

175

148

View full text Add to dashboard Cite

show abstract

“…Because APP CTFs impair Ca 2ϩ homeostasis, long-term potentiation, and inflammatory processes (Yankner et al, 1989;Berger-Sweeney et al, 1999;Lahiri et al, 2002;Chang and Suh, 2005), their accumulation could contribute to neuronal dysfunction in AD. Indeed, mice with PS deficiency in forebrain neurons show age-dependent accumulation of APP CTFs and neurodegeneration (Herms et al, 2003;Saura et al, 2004), which because of the lack of ␥-secretase could not be attributed to toxic effects of A␤.…”

Section: Discussionmentioning

confidence: 99%

Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

Tamboli¹,

Prager²,

Thal³

et al. 2008

J. Neurosci.

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Presenilins (PSs) are components of the ␥-secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that ␥-secretase is involved in the regulation of cellular lipoprotein uptake. Loss of ␥-secretase function decreased endocytosis of low-density lipoprotein (LDL) receptor. The decreased uptake of lipoproteins led to upregulation of cellular cholesterol biosynthesis by increased expression of CYP51 and enhanced metabolism of lanosterol. Genetic deletion of PS1 or transgenic expression of PS1 mutants that cause early-onset Alzheimer's disease led to accumulation of ␥-secretase substrates and mistargeting of adaptor proteins that regulate endocytosis of the LDL receptor. Consistent with decreased endocytosis of these receptors, PS1 mutant mice have elevated levels of apolipoprotein E in the brain. Thus, these data demonstrate a functional link between two major genetic factors that cause early-onset and late-onset Alzheimer's disease.

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“…Overproduced non‐Aβ APP fragments may interact unphysiologically with cellular proteins (Chang & Suh, 2005; Mitani et al , 2012; Nicolas & Hassan, 2014; Kerridge et al , 2015; Nhan et al , 2015; Willem et al , 2015; Xia et al , 2016). See Fig 3.…”

Section: Limitations Of First‐generation Mouse Modelsmentioning

confidence: 99%

APP mouse models for Alzheimer's disease preclinical studies

et al. 2017

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Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.

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Pathophysiological Roles of Amyloidogenic Carboxy-Terminal Fragments of the β-Amyloid Precursor Protein in Alzheimer’s Disease

Cited by 64 publications

References 99 publications

ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

APP mouse models for Alzheimer's disease preclinical studies

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