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1.
bioRxiv ; 2024 Jan 24.
Article in English | MEDLINE | ID: mdl-38328107

ABSTRACT

Mutations in presenilin-1 (PSEN1) are the most common cause of familial, early-onset Alzheimer's disease (AD), typically producing cognitive deficits in the fourth decade. A variant of APOE, APOE3 Christchurch (APOE3ch) , was found associated with protection from both cognitive decline and Tau accumulation in a 70-year-old bearing the disease-causing PSEN1-E280A mutation. The amino acid change in ApoE3ch is within the heparan sulfate (HS) binding domain of APOE, and purified APOEch showed dramatically reduced affinity for heparin, a highly sulfated form of HS. The physiological significance of ApoE3ch is supported by studies of a mouse bearing a knock-in of this human variant and its effects on microglia reactivity and Aß-induced Tau deposition. The studies reported here examine the function of heparan sulfate-modified proteoglycans (HSPGs) in cellular and molecular pathways affecting AD-related cell pathology in human cell lines and mouse astrocytes. The mechanisms of HSPG influences on presenilin- dependent cell loss and pathology were evaluated in Drosophila using knockdown of the presenilin homolog, Psn , together with partial loss of function of sulfateless (sfl) , a homolog of NDST1 , a gene specifically affecting HS sulfation. HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in cultured human cell lines, Drosophila , and mouse astrocytes. RNAi of Ndst1 reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants of APOE, APOE3 , and APOE4 . RNA-sequence analysis of human cells deficient in HS synthesis demonstrated effects on the transcriptome governing lipid metabolism, autophagy, and mitochondrial biogenesis and showed significant enrichment in AD susceptibility genes identified by GWAS. Neuron-directed knockdown of Psn in Drosophila produced cell loss in the brain and behavioral phenotypes, both suppressed by simultaneous reductions in sfl mRNA levels. Abnormalities in mitochondria, liposome morphology, and autophagosome-derived structures in animals with Psn knockdown were also rescued by simultaneous reduction of sfl. sfl knockdown reversed Psn- dependent transcript changes in genes affecting lipid transport, metabolism, and monocarboxylate carriers. These findings support the direct involvement of HSPGs in AD pathogenesis.

2.
High Alt Med Biol ; 12(3): 223-7, 2011.
Article in English | MEDLINE | ID: mdl-21962065

ABSTRACT

We performed this study to determine the prevalence of elevated D-dimer, a marker for deep venous thrombosis (DVT), in asymptomatic high altitude climbers. On-site personnel enrolled a convenience sample of climbers at Mt. Everest Base Camp (Nepal), elevation 5340 m (17,500 ft), during a single spring climbing season. Subjects were enrolled after descent to base camp from higher elevation. The subjects completed a questionnaire to evaluate their risk factors for DVT. We then performed a D-dimer test in asymptomatic individuals. If the D-dimer test was negative, DVT was considered ruled out. Ultrasound was available to perform lower-extremity compression ultrasounds to evaluate for DVT in case the D-dimer was positive. We enrolled 76 high altitude climbers. None had a positive D-dimer test. The absence of positive D-dimer tests suggests a low prevalence of DVT in asymptomatic high altitude climbers.


Subject(s)
Altitude Sickness/complications , Fibrin Fibrinogen Degradation Products/metabolism , Venous Thrombosis/blood , Venous Thrombosis/epidemiology , Adult , Altitude , Confidence Intervals , Female , Humans , Male , Middle Aged , Prevalence , Venous Thrombosis/etiology , Young Adult
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