Alzheimer’s breakthrough: Scientists discover the ‘ground zero’ of the disease in a vulnerable set of immune cells – paving the way to a cure

Alzheimer’s disease is caused by immune cells in the brain triggered by inflammation, according to a breakthrough discovery.

The new research could lead to the development of a drug that treats or even prevents the condition within five years, say scientists.

Experiments found destroying specific cells – known as microglia – reduced the formation of clumps of amyloid beta that form in Alzheimer’s and destroy memory.

These are the rogue proteins believed to lie at the root of the devastating neurological illness.

Human trials of all therapies have failed in the past. Most have targeted the amyloid plaques that build up in the brains of patients.

The German team say the breakthrough is exciting as it sheds fresh light on a classic hallmark of Alzheimer’s.

Experts have hailed the discovery by scientists at the University of Bonn, in Germany, as a major step in the fight against the crippling neurodegenerative disease (file image)
It also offers hope of an effective medication aimed at the ‘microglia’ cells – instead of amyloid-beta itself.

Prof Michael Heneka and colleagues say the amyloid beta plaques are fuelled by inflammation.

In Alzheimer’s patients these proteins collect together – leading to cell damage and confusion.

For years inflammation has been suspected of having a role but the exact nature of its involvement has been hard to pin down – until now.

The researchers found the microglia release specks of a protein called ASC in response to it. They stick to the amyloid beta protein – boosting its production.

Prof Heneka, of the University of Bonn, Germany, said this may even occur in the very early stages of Alzheimer’s.

In tests an antibody that blocked ASC from binding to amyloid beta stopped it from forming into damaging clumps.

The study published in Nature found this worked in live mice as well as cells grown in the laboratory.

ASC reside in a vital inflammatory pathway called the NLRP3 inflammasome which damages brain cells.

Prof Heneka said: ‘In patients with Alzheimer’s disease, deposition of amyloid-beta is accompanied by activation of the innate immune system and involves formation of ASC specks in microglia.’

These bind rapidly to amyloid-beta and increase the formation of clumps. He said ASC specks have been visualised in the brains of patients who died from Alzheimer’s.

He said: ‘The patho-physiological link between inflammasome responses and amyloid-beta plaque spreading suggests pharmacological targeting of inflammasomes could represent a novel treatment for Alzheimer’s disease.’

Mice genetically engineered to lack the NLRP3 gene that produces ASC showed much less amyloid-beta in the brain – and performed better on spatial memory tasks.

Antibodies to ASC – which prevent the specks from binding to other proteins – also suppressed the formation of amyloid-beta clumps.

Speaking from Germany, Prof Heneka said: ‘The hope would be to interfere with disease progression and spreading of pathology by counteracting or interfering with the NLRP3 inflammasome or ASC specks.

‘I would hope – given it is possible to develop a safe and brain penetrant NLRP3 inhibitor – this could be tested in the next five to 10 years from now.’

His lab had previously shown mice lacking the protein NLRP3 are less likely to develop clumps of amyloid-beta – suspected of lying at the heart of Alzheimer’s.

Prof Heneka said: ‘Spreading and disease progression is absent in the state of the art model of disease spreading.

‘If animals carry a genetic knockout for ASC one would hope blocking ASC speck formation holds therapeutic potential.’

Professor Richard Ransohoff, a cell biologist at Harvard Medical School, Boston,

reviewed the study for the journal and said the identification of specific chemicals in plaque formation is ‘extremely welcome.’

They ‘could accelerate the development of better therapies’ but if these are to be effective it will be important to discover which part to target.

He described suppressing formation of ASC specks as a specific ‘downstream aspect’ but this might not sufficiently inhibit all the problems implicated in Alzheimer’s.

Prof Ransohoff said: ‘Despite this difficulty, which bedevils all pathway directed therapeutics, it is heartening and invigorating to have a newly discovered mechanism to consider in the quest to treat Alzheimer’s disease.’

Last year University of Southampton researchers found increased numbers of microglia in the post mortem brains of people with Alzheimer’s.

A drug used to block their production in the brains of mice had fewer memory and behavioural problems.

The compound also prevented the loss of communication points between nerve cells in the brain – which usually happens in people with Alzheimer’s. Experts said the results were ‘exciting’.

About 850,000 people in Britain have dementia, with Alzheimer’s by far the most common form, with the figure set to reach a million by 2025 because of the ageing population. There is no cure.


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