The Role of Apolipoprotein E in Alzheimer's Disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

Genetic factors play a major role in determining a person's risk to develop Alzheimer's disease (AD). Rare mutations transmitted in a Mendelian fashion within affected families, for example, APP, PSEN1, and PSEN2, cause AD. In the absence of mutations in these genes, disease risk is largely determined by common polymorphisms that, in concert with each other and nongenetic risk factors, modestly impact risk for AD (e.g., the e4-allele in APOE). Recent genome-wide screening approaches have revealed several additional AD susceptibility loci and more are likely to be discovered over the coming years. In this chapter, we review the current state of AD genetics research with a particular focus on loci that now can be considered established disease genes. In addition to reviewing the potential pathogenic relevance of these genes, we provide an outlook into the future of AD genetics research based on recent advances in high-throughput sequencing technologies.

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The genetics of Alzheimer's disease.

Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis

Accumulations of insoluble deposits of amyloid β-peptide are major pathological hallmarks of Alzheimer disease. Amyloid β-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the β-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. β- and γ-secretase liberate by sequential cleavage the neurotoxic amyloid β-peptide, whereas α-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid β-peptide generation and therefore disease onset and progression.

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Trafficking and Proteolytic Processing of APP

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological changes, including the deposition of amyloid β (Aβ) in senile plaques. The mechanisms causing the disease and Aβ accumulation are not well understood, but important genetic associations with apolipoprotein E genotype and involvement of lipoprotein receptors have become apparent. LR11 (also known as SorLA), a member of the low-density lipoprotein receptor family, has been identified previously as an altered transcript in microarray analyses of samples from human AD cases. Here, we show neuronal expression of the lipoprotein receptor LR11 in control brain in regions vulnerable to AD neuropathology and marked reduction of LR11 expression in these regions in AD brains before cell death. Overexpression of LR11 drastically reduces levels of extracellular Aβ and also lowers levels of total cellular amyloid precursor protein (APP). LR11 colocalizes with APP and regulates its trafficking in endocytic compartments, which are important intracellular sites for APP processing and Aβ generation. Endogenous LR11 localizes to neuronal multivesicular bodies in both rat and human brain. The robust correlation between reduced LR11 expression and AD neuropathology and its potent effects on extracellular Aβ levels suggest that this neuronal lipoprotein receptor could play an important role in AD pathogenesis.

https://www.jneurosci.org/content/jneuro/26/5/1596.full.pdf

The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments.

The Lipoprotein Receptor LR11 Regulates Amyloid β Production and Amyloid Precursor Protein Traffic in Endosomal Compartments

Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease.

LR11 is an ApoE receptor that is enriched in the brain We have shown that LR11 is markedly downregulated in patients with sporadic Alzheimer disease (AD) This finding led us to explore whether reduced LR11 expression reflects a primary mechanism of disease or merely a secondary consequence of other AD-associated changes Therefore, LR11 expression was assessed in a transgenic mouse model of AD and familial AD (FAD) brains Immunohistochemistry and immunoblotting of LR11 in PS1/APP transgenic and wild-type mice indicated that LR11 levels are not affected by genotype or accumulation of amyloid pathology LR11 expression was also evaluated based on immunoblotting and LR11 immunostaining intensity in human frontal cortex in controls, sporadic AD, and FAD, including cases with presenilin-1 (PS1) and presenilin-2 (PS2) mutations Although LR11 was reduced in sporadic AD, there was no difference in protein level or staining intensity between control and FAD cases The finding that LR11 expression is unaffected in both a mouse model of AD and autosomal-dominant forms of AD suggests that LR11 is not regulated by amyloid accumulation or other AD neuropathologic changes We hypothesize that LR11 loss may be specific to sporadic AD and influence amyloid pathology through mechanisms independent of substrate-enzyme interactions regulated by FAD mutations

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LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease.

Alzheimer9s disease (AD) is the most prevalent form of dementia, resulting in progressive neuronal death and debilitating damage to brain loci that mediate memory and higher cognitive function. While pathogenic genetic mutations have been implicated in ∼2% of AD cases, the proximal events that underlie the common, sporadic form of the disease are incompletely understood. Converging lines of evidence from human neuropathology, basic biology, and genetics have implicated loss of the multifunctional receptor LR11 (also known as SORLA and SORL1) in AD pathogenesis. Cell-based studies suggest that LR11 reduces the formation of β-amyloid (Aβ), the molecule believed to be a primary toxic species in AD. Recently, mutant mice deficient in LR11 were shown to upregulate murine Aβ in mouse brain. In the current study, LR11-deficient mice were crossed with transgenic mice expressing autosomal-dominant human AD genes, presenilin-1 (PS1ΔE9) and amyloid precursor protein (APPswe). Here, we show that LR11 deficiency in this AD mouse model significantly increases Aβ levels and exacerbates early amyloid pathology in brain, causing a forward shift in disease onset that is LR11 gene dose-dependent. Loss of LR11 increases the processing of the APP holo-molecule into α-, β-, and γ-secretase derived metabolites. We propose that LR11 regulates APP processing and Aβ accumulation in vivo and is of proximal importance to the cascade of pathological amyloidosis. The results of the current study support the hypothesis that control of LR11 expression may exert critical effects on Alzheimer9s disease susceptibility in humans.

https://www.jneurosci.org/content/jneuro/28/48/12877.full.pdf

Sara E. Dodson

Papers

The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments.

The Lipoprotein Receptor LR11 Regulates Amyloid β Production and Amyloid Precursor Protein Traffic in Endosomal Compartments

Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease.

LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease.

Loss of LR11/SORLA Enhances Early Pathology in a Mouse Model of Amyloidosis: Evidence for a Proximal Role in Alzheimer’s Disease