Impaired energy metabolism linked with initiation of plaques in Alzheimer's brain

Dec 24, 2008

Scientists have identified an initiating molecular mechanism in sporadic Alzheimer's disease (AD). The study, published by Cell Press in the December 26th issue of the journal Neuron, provides new information about generation of damaging amyloid β (Aβ) plaques within the AD brain and underscores the importance of developing new preventative and disease-modifying therapies for AD, especially those aimed at interrupting pathological Aβ-production.

AD, the leading cause of dementia in the elderly, is a devastating neurological disorder characterized by accumulation and deposition of sticky clumps of Aβ protein. Aβ protein is generated from amyloid precursor protein (APP) by β-site APP cleaving enzyme (BACE1). Previous research has suggested that BACE1 activity may play a key role in the initiation of AD pathogenesis and identified BACE1 as a promising target for AD therapeutics.

Recently, BACE1 was linked to cellular stress responses in the brain. Importantly, the AD brain exhibits impaired energy metabolism (a stressful situation) and it has been suggested that diminished cerebral use of glucose and oxygen may be an early event in AD pathogenesis.

Senior study author Dr. Robert Vassar from Northwestern University Feinberg School of Medicine has explored the link between energy inhibition and AD pathogenesis. "We have shown previously, using a pharmacological model of energy metabolism inhibition in pre-plaque transgenic mice with an excess of APP, that BACE1 and Aβ levels are elevated in the brain," says Dr. Vassar.

Dr. Vassar and colleagues expanded on their previous work by using glucose deprivation to examine the molecular mechanisms underlying elevated BACE1 levels in response to energy inhibition. They found that glucose deprivation caused an increase in BACE1 levels and led to the phosphorylation of the stress-inducible translation initiation factor, eIF2?. Further, direct phosphorylation of eIF2? increased BACE1 levels and enhanced Aβ production while inhibition of eIF2? phosphorylation prevented energy-deprivation induced increases in BACE1.

The researchers went on to show that energy inhibition increased eIF2? phosphorylation, BACE1 levels and amyloid plaque formation in APP transgenic mice. In addition, phosphorylated eIF2? and BACE1 were elevated in an aggressive A? plaque-forming mouse model and in humans with AD.

"Here, for the first time we provide evidence linking impaired energy metabolism, an AD-relevant stress, with BACE1 translation mediated by eIF2? phosphorylation," says Dr. Vassar. "Our findings implicate phosphorylated eIF2? in both the initiation and progression of sporadic AD. Future experiments will determine whether inhibition of eIF2? phosphorylation could be an efficacious therapeutic approach for the prevention and treatment of AD."

Source: Cell Press

Explore further: Fatigue, fear are daily lot of Ebola fighters: experts

add to favorites email to friend print save as pdf

Related Stories

Japan wraps up Pacific whale hunt

38 minutes ago

Japan announced Tuesday that it had wrapped up a whale hunt in the Pacific, the second campaign since the UN's top court ordered Tokyo to halt a separate slaughter in the Antarctic.

Researchers uncover secrets of internal cell fine-tuning

48 minutes ago

New research from scientists at the University of Kent has shown for the first time how the structures inside cells are regulated – a breakthrough that could have a major impact on cancer therapy development.

Local education politics 'far from dead'

48 minutes ago

Teach for America, known for recruiting teachers, is also setting its sights on capturing school board seats across the nation. Surprisingly, however, political candidates from the program aren't just pushing ...

Recommended for you

Fatigue, fear are daily lot of Ebola fighters: experts

1 hour ago

Doctors, nurses and hospital workers fighting the Ebola epidemic in west Africa are struggling with a daily burden of exhaustion, shortage of staff and fear for themselves over the deadly virus, specialists say.

Hong Kong makes Ebola 'contingency' measures

4 hours ago

Hong Kong said Wednesday it was quarantining all people from Guinea, Sierra Leone and Liberia who were showing Ebola-like symptoms on arrival in the city, as fears grow worldwide about the spread of the deadly virus.

EU ready for Ebola threat: sources

7 hours ago

The European Union is equipped and ready to treat victims should the deadly Ebola virus, which has killed hundreds in West Africa, be found in member states, EU sources said Wednesday.

Reducing kidney injury using a quality improvement method

11 hours ago

Using quality improvement measures in eight of the 10 hospitals in the Northern New England Cardiovascular Disease Study Group, researchers have found a way to reduce kidney injury in patients undergoing a procedure with ...

App for headache sufferers shows success

23 hours ago

A unique app that helps headache sufferers to record the severity and regularity of their pain is being used as part of a Griffith research study.

User comments : 0