Reduction of Synaptojanin 1 Accelerates Aβ Clearance and Attenuates Cognitive Deterioration in an Alzheimer Mouse Model

Zhu, Li; Zhong, Minghao; Zhao, Jichun; Rhee, Hannah; Caesar, Ina; Knight, Elysse M.; Volpicelli‐Daley, Laura A.; Bustos, Victor; Netzer, William J.; Liu, Lijuan; Lucast, Louise; Ehrlich, Michelle E.; Robakis, Nikolaos K.; Gandy, Samuel E.; Cai, Dongming

doi:10.1074/jbc.m113.504365

Cited by 63 publications

(73 citation statements)

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“…One such pathway may be aberrant metabolism of membrane phospholipids. Recent literature, including data from our laboratory, suggests that PI homeostasis, particularly PIP 2 , plays an important role in AD (10,22,24,28,29). For example, one study demonstrated PIP 2 reduction in the prefrontal cortex of patients with AD (29).…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence indicates that phospholipid regulators including synj1 (22)(23)(24), phospholipase D (25), and PI-binding clathrin assembly protein (26) play important roles in pathways leading to neurodegenerative processes such as lipid granule accumulation, endosomal/lysosomal degradation, and regulation of microglia and astrocyte functions. Our data show that ApoE3 increases brain PIP 2 levels through promotion of synj1 mRNA degradation and suppression of synj1 expression.…”

Section: Discussionmentioning

confidence: 99%

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Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

Zhu

Zhong

Elder

et al. 2015

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

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115

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The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer's disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP 2 ) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP 2 -degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP 2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.Alzheimer's disease | apolipoprotein E4 | phospholipid | dysregulation | cognitive deficits

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

Zhu

Zhong

Elder

et al. 2015

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

Self Cite

115

100

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“…A reduction in the dose of the chromosome 21 gene cystatin B (CSTB), which encodes an endogenous inhibitor of lysosomal cathepsins, decreases the accumulation of Aβ and associated cognitive deficits 147 . Overexpression of another chromosome 21 gene, synaptojanin 1 (SYNJ1), which encodes a phosphoinositide phosphatase that regulates levels of membrane phosphatidylinositol-4,5-bisphosphate, has been associated with endosomal enlargement 148 , whereas reduced expression of SYNJ1 lowers Aβ accumulation, as well as neuronal dysfunction and cognitive deficits 149,150 . How endosomal enlargement caused by trisomy contributes to neuronal dysfunction and degeneration is another important area for future research.…”

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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“…For example, herbal medicines and isolated compounds have been [191][192][193] and of diabetic neuropathy 194 . Here, we will focus on two major areas: antimicrobials, and modulators of protein protein interactions.…”

Section: Opportunities For Natural Productsmentioning

confidence: 99%

The re-emergence of natural products for drug discovery in the genomics era

Harvey

Edrada-Ebel

Quinn

2015

Nat Rev Drug Discov

2,113

1,410

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Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review advances in chemical techniques for the isolation and structural elucidation of natural products that have reduced these technological barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

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Reduction of Synaptojanin 1 Accelerates Aβ Clearance and Attenuates Cognitive Deterioration in an Alzheimer Mouse Model

Cited by 63 publications

References 50 publications

Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

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

The re-emergence of natural products for drug discovery in the genomics era

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