LDL receptor-related protein (LRP) in Alzheimer's disease: Towards a unified theory of pathogenesis

Uden, Emily Van; Kang, David E.; Koo, Edward H.; Masliah, Eliezer

doi:10.1002/1097-0029(20000815)50:4<268::aid-jemt3>3.0.co;2-1

Cited by 38 publications

(15 citation statements)

References 112 publications

(123 reference statements)

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“…LRP is a neuronal receptor for several ligands believed to be important in AD pathogenesis including apolipoprotein E (apoE) and APP (14,27). Here, we showed that neuronal overexpression of a functional minireceptor of LRP (mLRP2) increased soluble levels of brain A␤ in PDAPP mice in an age-dependent manner.…”

Section: Discussionmentioning

confidence: 92%

“…LRP is an Ϸ600-kDa cell-surface endocytic receptor member of the LDL receptor family (13). LRP is highly expressed in the brain and is considered the major neuronal receptor for apolipoprotein E (apoE) and ␣ 2 -macroglobulin (␣ 2 M), also implicated in the pathogenesis of AD by both biochemical and genetic evidence (14).A putative role for LRP in AD is supported by in vitro studies showing that apoE and ␣ 2 M can form stable complexes with A␤ and promote its clearance via cell-surface LRP (5-10). Furthermore, LRP appears to influence APP endocytic trafficking and cellular distribution such that processing to A␤ and its extracellular release are enhanced (11,12).…”

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confidence: 99%

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confidence: 99%

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Increased soluble amyloid-β peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein

Zerbinatti

Wozniak²,

Cirrito

et al. 2004

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

127

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Amyloid-␤ peptide (A␤) is central to the pathogenesis of Alzheimer's disease, and the low-density lipoprotein receptor-related protein (LRP) has been shown to alter A␤ metabolism in vitro. Here, we show that overexpression of a functional LRP minireceptor in the brain of PDAPP mice results in age-dependent increase of soluble brain A␤, with no changes in A␤ plaque burden. Importantly, soluble brain A␤ was found to be primarily in the form of monomers͞dimers and to be highly correlated with deficits in spatial learning and memory. These results provide in vivo evidence that LRP may contribute to memory deficits typical of Alzheimer's disease by modulating the pool of small soluble forms of A␤.A lzheimer's disease (AD) is characterized by cognitive impairment and neuronal loss that have been primarily linked to the accumulation of extracellular neuritic plaques and intracellular neurofibrillary tangles in the brain (1). The major component of neuritic plaques is amyloid-␤ peptide (A␤), which is derived from the cleavage of amyloid precursor protein (APP). Accumulation of fibrillar aggregates of A␤ in the brain parenchyma, caused by A␤ overproduction, impaired clearance, or both, is the basis for the amyloid cascade hypothesis long proposed to explain the etiology of AD (2).The low-density lipoprotein (LDL) receptor-related protein (LRP) has been genetically linked to AD (3, 4) and has been shown to influence A␤ metabolism in vitro (5-12). LRP is an Ϸ600-kDa cell-surface endocytic receptor member of the LDL receptor family (13). LRP is highly expressed in the brain and is considered the major neuronal receptor for apolipoprotein E (apoE) and ␣ 2 -macroglobulin (␣ 2 M), also implicated in the pathogenesis of AD by both biochemical and genetic evidence (14).A putative role for LRP in AD is supported by in vitro studies showing that apoE and ␣ 2 M can form stable complexes with A␤ and promote its clearance via cell-surface LRP (5-10). Furthermore, LRP appears to influence APP endocytic trafficking and cellular distribution such that processing to A␤ and its extracellular release are enhanced (11,12). To assess the effect of LRP on A␤ deposition in vivo, we generated transgenic (TG) mice that overexpress a functional minireceptor of LRP in the brain. We bred LRP TG mice to PDAPP TG mice, an animal model that develops amyloid plaques similar to those seen in AD (15). Although brain A␤ plaque burden was not significantly altered by the overexpression of LRP, double TG mice showed an age-dependent increase of soluble brain A␤ levels when compared to littermate mice overexpressing APP alone. The A␤ levels in this soluble brain extracts, which we found to be mostly A␤ monomers and dimers, were highly correlated with deficits in spatial learning and memory. These data provide strong evidence that, in addition to A␤ plaques, small soluble forms of A␤ appear to impair neuronal function and contribute to memory deficits in vivo. Materials and MethodsAnimals and Tissue Preparation. mLRP2 TG mice were generated in a B6͞C3H backgr...

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

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Increased soluble amyloid-β peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein

Zerbinatti

Wozniak²,

Cirrito

et al. 2004

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

127

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“…More recently, Sehgal and colleagues reported that an extract of Withania somnifera induces a rapid clearance of amyloid pathology with a co-incident induction of LRP1 expression in liver [14]. Other proteins implicated in amyloidogenesis have been identified as interacting with LRP1 [15], such as apolipoprotien E (ApoE) and α2-macroglobulin. Both of these proteins are ligands of LRP1 and have been reported to mediate the clearance of Aβ [13,16-19].…”

Section: Introductionmentioning

confidence: 99%

Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice

Green

Fromholt

et al. 2012

Alzheimers Res Ther

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IntroductionThe low-density lipoprotein receptor-related protein (LRP1) and its family members have been implicated in the pathogenesis of Alzheimer's disease. Multiple susceptibility factors converge to metabolic pathways that involve LRP1, including modulation of the processing of amyloid precursor protein (APP) and the clearance of Aβ peptide.MethodsWe used the Cre-lox system to lower LRP1 levels in hippocampal neurons of mice that develop Alzheimer-type amyloid by crosses between mice that express Cre recombinase under the transcriptional control of the GFAP promoter, mice that harbor loxp sites in the LRP1 gene, and the APPswe/PS1dE9 transgenic model. We compared amyloid plaque numbers in APPswe/PS1dE9 mice lacking LRP1 expression in hippocampus (n = 13) to mice with normal levels of LRP1 (n = 12). Student t-test was used to test whether there were significant differences in plaque numbers and amyloid levels between the groups. A regression model was used to fit two regression lines for these groups, and to compare the rates of Aβ accumulation.ResultsImmunohistochemical analyses demonstrated efficient elimination of LRP1 expression in the CA fields and dentate gyrus of the hippocampus. Within hippocampus, we observed no effect on the severity of amyloid deposition, the rate of Aβ40/42 accumulation, or the architecture of amyloid plaques when LRP1 levels were reduced.ConclusionsExpression of LRP1 by neurons in proximity to senile amyloid plaques does not appear to play a major role in modulating the formation of these proximal deposits or in the appearance of the associated neuritic pathology.

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“…The mechanism of acquiring sulfatides by apoE particles is still unknown, which may be through a “kiss-and-run” mechanism or through a sulfatide carrier protein including apoE itself. In the working model, these nascent sulfatide-containing apoE-associated lipoprotein particles are then metabolized and degraded through an endocytotic pathway by neuronal cells possessing one or more members of the LDL receptor superfamily (e.g., LRP) [55, 56]. Under normal physiological conditions, the majority of the internalized sulfatides are catabolized to various degradation products (e.g., sulfate, galactose, trans -hexadecenal, sphingosine, etc.)…”

Section: Association Of Sulfatides With Apoe Particles In the Cnsmentioning

confidence: 99%

The Pathogenic Implication of Abnormal Interaction Between Apolipoprotein E Isoforms, Amyloid-beta Peptides, and Sulfatides in Alzheimer’s Disease

Han

2010

Mol Neurobiol

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Alzheimer's disease (AD) is the most common cause of dementia in the aging population. Prior work has shown that the ε4 allele of apolipoprotein E (apoE4) is a major risk factor for "sporadic" AD, which accounts for >99% of AD cases without a defined underlying mechanism. Recently, we have demonstrated that sulfatides are substantially and specifically depleted at the very early stage of AD. To identify the mechanism(s) of sulfatide loss concurrent with AD onset, we have found that: (1) sulfatides are specifically associated with apoE-associated particles in cerebrospinal fluid (CSF); (2) apoE modulates cellular sulfatide levels; and (3) the modulation of sulfatide content is apoE isoform dependent. These findings not only lead to identification of the potential mechanisms underlying sulfatide depletion at the earliest stages of AD but also serve as mechanistic links to explain the genetic association of apoE4 with AD. Moreover, our recent studies further demonstrated that (1) apoE mediates sulfatide depletion in amyloid-β precursor protein transgenic mice; (2) sulfatides enhance amyloid β (Aβ) peptides binding to apoE-associated particles; (3) Aβ42 content notably correlates with sulfatide content in CSF; (4) sulfatides markedly enhance the uptake of Aβ peptides; and (5) abnormal sulfatide-facilitated Aβ uptake results in the accumulation of Aβ in lysosomes. Collectively, our studies clearly provide a link between apoE, Aβ, and sulfatides in AD and establish a foundation for the development of effective therapeutic interventions for AD.

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LDL receptor-related protein (LRP) in Alzheimer's disease: Towards a unified theory of pathogenesis

Cited by 38 publications

References 112 publications

Increased soluble amyloid-β peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein

Increased soluble amyloid-β peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein

Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice

The Pathogenic Implication of Abnormal Interaction Between Apolipoprotein E Isoforms, Amyloid-beta Peptides, and Sulfatides in Alzheimer’s Disease

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