Faulty cellular ‘garbage disposal’ implicated in Alzheimer’s

2 Jul

One of the hallmarks of Alzheimer’s disease is deposits of beta-amyloid – a

faulty protein – in the brain. Surrounding these deposits or plaques are abnormally

high numbers of lysosomes, tiny specialized systems that digest and dispose of

cellular garbage.

Lysosomes – in magenta – accumulate near amyloid plaques.

Alzheimer’s disease is the most common form of dementia. It affects the part of

the brain that controls thought, memory and language.

The disease begins with mild memory loss and progresses to the point where the

person affected struggles to carry on a conversation and respond to what is

happening around them.

According to the Centers for Disease Control and Prevention, in 2013, as many as

5 million Americans aged 65 years or older had Alzheimer’s disease, and the number

is expected to rise to 13.8 million by 2050.

When scientists first found – around 50 years ago – that beta-amyloid deposits

in the brains of people with Alzheimer’s disease were surrounded by massive

accumulations of lysosomes, they assumed they were there to help degrade and clear

away the faulty protein.

Now, a new study from Yale University of New Haven, CT, suggests not only is it

not as straightforward as this, but the opposite could be happening.

The Yale team found that the lysosomes surrounding the deposits of

beta-amyloid are faulty, and instead of working against Alzheimer’s progression,

may even be contributing to it.

The researchers report their findings in the Proceedings of the National

Academy of Sciences.

They suggest the discovery could lead to new types of treatment that correct the

faulty lysosomes so they can do their job properly, clear away the beta-amyloid

and stop it clogging the brain.

Vicious cycle

In the study paper, the Yale team describes how the lysosomes build up in swollen axons or nerve

fibers that contact the amyloid deposits outside the brain cells.

They found that the lysosomes have abnormally high levels of beta-secretase, the

enzyme that triggers the production of the toxic beta-amyloid protein.

The researchers suggest the faulty lysosomes are not able to break down the

enzyme because they are not fully mature. To become mature, they have to travel

along the axons. But the beta-amyloid plaques block their ability to do this, which

results in more accumulation of beta-secretase, which in turn triggers more beta-amyloid.

First author Swetha Gowrishankar, a postdoctoral scientist in the lab of senior

author Shawn Ferguson, assistant professor of cell biology, sums up the


“We think this represents a vicious circle.”

Put simply, to be able to do their job of eliminating the enzyme that boosts

Alzheimer’s plaques, the lysosomes have to be able to travel and mature. But their

means to do this is blocked by Alzheimer’s plaques.

The team now plans to test in mice engineered to develop Alzheimer’s whether

tweaking genes to help the faulty lysosomes digest the beta-secretase protects

against disease progression.

Faulty lysosomes have also been implicated in other neurodegenerative

diseases including Parkinson’s and frontotemporal dementia, they note.

Funding for the study came from the Howard Hughes Medical Institute, the Ellison

Medical Foundation, the National Institutes of Health, and the Consortium for

Frontotemporal Dementia Research.

Meanwhile, Medical News Today recently learned how high blood sugar may contribute to Alzheimer’s

disease by speeding up the production of beta-amyloid. A study conducted in mice

found that a doubling of blood glucose led to 20% higher levels of the protein.

Written by Catharine Paddock PhD