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Increased APOE abundance in the brain in Down syndrome - Alzheimer’s disease compared with early onset-Alzheimer's disease is associated with elevated APP and its processing products

ABSTRACT: Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimer’s disease (AD). Here we compare the proteome of the frontal cortex of people who have Down syndrome-Alzheimer’s disease (DSAD) with demographically matched cases of early-onset AD and healthy ageing controls from the general population. We find the abundance of several chromosome 21 encoded proteins are increased in DSAD compared to both comparative groups. Moreover, wider dysregulation of the proteome occurs beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD protein APOE, in people with DSAD compared to matched cases of early-onset AD.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Down Syndrome,Alzheimer's Disease

SUBMITTER: Cliona Farrell

LAB HEAD: Frances K Wiseman

PROVIDER: PXD058779 | Pride | 2025-02-26

REPOSITORIES: pride

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			Action	DRS
	20211019_CM_CF_DSAD1_1.raw.zip	Raw
	20211019_CM_CF_DSAD1_2.raw.zip	Raw
	20211019_CM_CF_DSAD1_3.raw.zip	Raw
	20211019_CM_CF_DSAD1_4.raw.zip	Raw
	20211019_CM_CF_DSAD2_1.raw.zip	Raw

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Project description:Approximately 35 million people worldwide suffer from Alzheimer’s disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (A) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3xTgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic A monomer with a concomitant decrease in toxic oligomer A load, compared to vehicle-treated 3xTgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD. Male 3xTgAD mice, 14 months of age, were maintained on a 12hr light dark cycle in pathogen free conditions. Animals received food and water ad libitum. The test group received 100ug/g body weight amitriptyline-hydrochloride per os in their drinking water (Sigma-Aldrich, St. Louis MO) for 4 months (n = 15), and the control group received water (n = 15). The Hippocampus and Cortex were removed from 3 replicates of each group and RNA purification was done using glass bead disruption followed by the RNEasy Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. The RNA was examined for quantity and quality using an Agilent Bioanalyzer 2100 (Agilent Technologies, Palo Alto, CA). The samples were hybridized to Illumina's SentrixMouse Ref-8 v2. Expression BeadChips (Illumina, San Diego, CA).

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Increased APOE abundance in the brain in Down syndrome - Alzheimer’s disease compared with early onset-Alzheimer's disease is associated with elevated APP and its processing products

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