UNDERSTANDING TRAFFIC JAMS IN ALZHEIMER’S.
Alzheimer’s disease (AD) is characterized by exaggerated protein accumulation in the extracellular milieu in the brain. The endosomal pathway is responsible for the secretion of proteins after cleavage, and defective endosomal pathway contributes to AD pathogenesis. However, which proteins are affected by defective endosomal pathway is still unclear. Now, Simoes et al. performed proteomic analysis in CSF from mice with defective endosomal trafficking and validated their findings in patients with AD and showed that APLP1 and CHL1 expression were increased and correlated with tau expression. The results provide precious insight regarding the effect of endosomal trafficking alterations in AD.
ABSTRACT
Endosomal trafficking has emerged as a defective biological pathway in Alzheimer’s disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the identity of the CSF proteins that accumulate in the setting of defects in AD’s endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD. We then validated three of the most relevant proteomic findings: the amino terminus of the transmembrane proteins APLP1 and CHL1, and the middomain of tau, which is known to be unconventionally secreted and elevated in AD. In patients with AD dementia, the concentration of amino-terminal APLP1 and CHL1 in the CSF correlated with tau and phosphorylated tau. Similar results were observed in healthy controls, where both proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD. Collectively, the mouse-tohuman studies suggest that retromerdependent endosomal trafficking can regulate tau, APLP1, and CHL1 CSF concentration, informing on how AD’s trafficking pathway might contribute to disease spread and how to identify its trafficking impairments in vivo.
INTRODUCTION
The abnormal accumulation of extracellular proteins is a hallmark feature of Alzheimer’s disease (AD), as typified by the cleaved fragments of the amyloid precursor protein (APP) and the microtubule binding protein tau. APP is cleaved in the endosome (1, 2), and its fragments are secreted through the endosomal pathway, representing an example of so-called unconventional secretion. Although it is now understood that tau is unconventionally secreted from neurons via direct translocation across the plasma membrane (3, 4), the mechanisms underlying active secretion of tau fragments (5) remain largely unknown. Recent genomic studies have identified endosomal trafficking as a biological pathway pathogenic in AD, and subsequent data have established that the defective pathway manifests as endosomal traffic jams (6).
Some of the best evidence in support of this conclusion is provided by molecules related to retromer, a multimodular protein assembly that is considered the “master conductor” of sorting and trafficking cargo out of the endosome (7). For example, mutations in SORL1, encoding a key retromer receptor in the brain (1, 8), are causally pathogenic in AD (9, 10). In addition, the core retromer protein VPS35 is deficient in regionally vulnerable AD brains (11), and a rare de novo mutation in VPS35 has been identified in AD (12), as have variants in a range of other retromer-related genes (13). Retromerdependent endosomal trafficking has been linked to many of AD’s core features (14)—including amyloid pathology (11, 14–17), tau pathology (18), glial pathology (19, 20), and the enlargement of neuronal endosomes (15,21–23)
Reference: https://pubmed.ncbi.nlm.nih.gov/33239387/
Alzheimer’s disease (AD) is characterized by exaggerated protein accumulation in the extracellular milieu in the brain. The endosomal pathway is responsible for the secretion of proteins after cleavage, and defective endosomal pathway contributes to AD pathogenesis. However, which proteins are affected by defective endosomal pathway is still unclear. Now, Simoes et al. performed proteomic analysis in CSF from mice with defective endosomal trafficking and validated their findings in patients with AD and showed that APLP1 and CHL1 expression were increased and correlated with tau expression. The results provide precious insight regarding the effect of endosomal trafficking alterations in AD.
ABSTRACT
Endosomal trafficking has emerged as a defective biological pathway in Alzheimer’s disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the identity of the CSF proteins that accumulate in the setting of defects in AD’s endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD. We then validated three of the most relevant proteomic findings: the amino terminus of the transmembrane proteins APLP1 and CHL1, and the middomain of tau, which is known to be unconventionally secreted and elevated in AD. In patients with AD dementia, the concentration of amino-terminal APLP1 and CHL1 in the CSF correlated with tau and phosphorylated tau. Similar results were observed in healthy controls, where both proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD. Collectively, the mouse-tohuman studies suggest that retromerdependent endosomal trafficking can regulate tau, APLP1, and CHL1 CSF concentration, informing on how AD’s trafficking pathway might contribute to disease spread and how to identify its trafficking impairments in vivo.
INTRODUCTION
The abnormal accumulation of extracellular proteins is a hallmark feature of Alzheimer’s disease (AD), as typified by the cleaved fragments of the amyloid precursor protein (APP) and the microtubule binding protein tau. APP is cleaved in the endosome (1, 2), and its fragments are secreted through the endosomal pathway, representing an example of so-called unconventional secretion. Although it is now understood that tau is unconventionally secreted from neurons via direct translocation across the plasma membrane (3, 4), the mechanisms underlying active secretion of tau fragments (5) remain largely unknown. Recent genomic studies have identified endosomal trafficking as a biological pathway pathogenic in AD, and subsequent data have established that the defective pathway manifests as endosomal traffic jams (6).
Some of the best evidence in support of this conclusion is provided by molecules related to retromer, a multimodular protein assembly that is considered the “master conductor” of sorting and trafficking cargo out of the endosome (7). For example, mutations in SORL1, encoding a key retromer receptor in the brain (1, 8), are causally pathogenic in AD (9, 10). In addition, the core retromer protein VPS35 is deficient in regionally vulnerable AD brains (11), and a rare de novo mutation in VPS35 has been identified in AD (12), as have variants in a range of other retromer-related genes (13). Retromerdependent endosomal trafficking has been linked to many of AD’s core features (14)—including amyloid pathology (11, 14–17), tau pathology (18), glial pathology (19, 20), and the enlargement of neuronal endosomes (15,21–23)
Reference: https://pubmed.ncbi.nlm.nih.gov/33239387/
