Summary: DDT exposure causes sodium channels to remain open, leading to increased neural firing and an increased release of amyloid beta peptide. Blocking the channels with tetrodotoxin reduces the toxic amyloid protein by increasing the production of the amyloid precursor protein.

Source: FAU

A new study led by researchers from Florida International University (FIU) reveals a mechanism linking the pesticide DDT to Alzheimer’s disease.

Published in Environmental Health Perspectives, the study shows how the persistent environmental pollutant DDT causes increased amounts of toxic amyloid beta, which form the characteristic amyloid plaques found in the brains of those with Alzheimer’s disease.

According to Jason Richardson, professor at FIU’s Robert Stempel College of Public Health & Social Work and corresponding author, the study further demonstrates that DDT is an environmental risk factor for Alzheimer’s disease.

In 2014, he led a team of scientists at Rutgers University, Emory University, and UT Southwestern Medical School who presented evidence linking DDT to the disease.

Now, they have data demonstrating a mechanism that may explain the association. “The vast majority of research on the disease has been on genetics—and genetics are very important—but the genes that actually cause the disease are very rare,” Richardson says.

“Environmental risk factors like exposure to DDT are modifiable. So, if we understand how DDT affects the brain, then perhaps we could target those mechanisms and help the people who have been highly exposed.”

DDT was extensively used between the 1940s and 1970s to combat insect-borne diseases like malaria and treat crop and livestock production. People highly exposed to DDT back then are now beginning or already in the range of ages with a higher risk for developing Alzheimer’s disease.

Although banned in the U.S., DDT exposure is likely possible today from legacy contamination or imported foods. The study focused on sodium channels, which the nervous system uses to communicate between brain cells (neurons), as the potential mechanism.

DDT causes these channels to remain open, leading to increased firing of neurons and increased release of amyloid-beta peptides.

In the study, researchers demonstrate that if neurons are treated with tetrodotoxin, a compound that blocks sodium channels in the brain, the increased production of the amyloid precursor protein and toxic amyloid-beta species is prevented.

“This finding could potentially provide a roadmap to future therapies for people highly exposed to DDT,” Richardson says.

How DDT Exposure Contributes to Alzheimer’s Disease Risk

DDT was extensively used between the 1940s and 1970s to combat insect-borne diseases like malaria and treat crop and livestock production. Image is in the public domain

The study was done in collaboration with Rutgers University. Researchers used cultured cells, transgenic flies, and mice models to demonstrate DDT’s effect on the amyloid pathway, a hallmark of Alzheimer’s disease.

By exposing all the models to DDT—in the range of what people were exposed to decades ago—researchers observed an increase in the production of the amyloid precursor protein, as well as elevated levels of toxic amyloid species, such as amyloid-beta peptides, and plaques.

“We found that if we block sodium channels with the compound tetrodotoxin and then dose neurons with DDT, then they don’t increase the amyloid precursor protein and don’t secrete excess amyloid-beta,” Richardson says.

The next step for the researchers will be to test therapeutic drugs using the information they now know. Richardson shares that there already are several drugs that target sodium channels.

“We are in the process of doing those studies to see if we can take an already FDA-approved drug and see if it reduces toxic amyloid accumulation,” he adds.

About this environmental neuroscience and Alzheimer’s disease research news

Author: Press OfficeSource: FAUContact: Press Office – FAU
Image: The image is in the public domain

Original Research: Open access.
“Effects of DDT on Amyloid Precursor Protein Levels and Amyloid Beta Pathology: Mechanistic Links to Alzheimer’s Disease Risk” by Aseel Eid et al. Environmental Health Perspectives


Abstract

Effects of DDT on Amyloid Precursor Protein Levels and Amyloid Beta Pathology: Mechanistic Links to Alzheimer’s Disease Risk

Background:

The interaction of aging-related, genetic, and environmental factors is thought to contribute to the etiology of late-onset, sporadic Alzheimer’s disease (AD). We previously reported that serum levels of p,p′-dichlorodiphenyldichloroethylene (DDE), a long-lasting metabolite of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT), were significantly elevated in patients with AD and associated with the risk of AD diagnosis. However, the mechanism by which DDT may contribute to AD pathogenesis is unknown.

Objectives:

This study sought to assess effects of DDT exposure on the amyloid pathway in multiple in vitro and in vivo models.

Methods:

Cultured cells (SH-SY5Y and primary neurons), transgenic flies overexpressing amyloid beta (AβAβ), and C57BL/6J and 3xTG-AD mice were treated with DDT to assess impacts on the amyloid pathway. Real time quantitative polymerase chain reaction, multiplex assay, western immunoblotting and immunohistochemical methods were used to assess the effects of DDT on amyloid precursor protein (APP) and other contributors to amyloid processing and deposition.

Results:

Exposure to DDT revealed significantly higher APP mRNA and protein levels in immortalized and primary neurons, as well as in wild-type and AD-models. This was accompanied by higher levels of secreted AβAβ in SH-SY5Y cells, an effect abolished by the sodium channel antagonist tetrodotoxin. Transgenic flies and 3xTG-AD mice had more AβAβ pathology following DDT exposure. Furthermore, loss of the synaptic markers synaptophysin and PSD95 were observed in the cortex of the brains of 3xTG-AD mice.

Discussion:

Sporadic Alzheimer’s disease risk involves contributions from genetic and environmental factors. Here, we used multiple model systems, including primary neurons, transgenic flies, and mice to demonstrate the effects of DDT on APP and its pathological product AβAβ. These data, combined with our previous epidemiological findings, provide a mechanistic framework by which DDT exposure may contribute to increased risk of AD by impacting the amyloid pathway.

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