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Alzheimer’s disease has been reversed in mice with a drug that targets the brain’s immune cells.
The breakthrough could lead to a cure for the devastating neurological illness, say scientists.
Experiments found blocking the production of cells known as microglia kept grey matter healthy.
Found in the brain and spinal cord, they control the immune system of the central nervous system.
It adds to a growing body of evidence that dementia is driven by inflammation – caused by a build up of microglia.
Previous studies have found high levels of the cells in the post-mortem brains of people with Alzheimer’s.
They are “the linchpin of the neurodegenerative process,” according to the US team. Up until now the focus has been on a rogue protein called tau.
In Alzheimer’s it forms into tangles, destroying neurons. But the process is fuelled by microglia, said senior author Professor David Holtzman,
The findings could lead to new treatments for dementia and other tau linked illnesses such as chronic traumatic encephalopathy (CTE) and Parkinson’s disease.
The compound used on the lab rodents has side effects – making it unsuitable for humans. But it opens the door to others that singles out microglia.
Prof Holtzman, a neurologist at Washington University, St Louis, said: “If you could target microglia in some specific way and prevent them from causing damage, I think that would be a really important, strategic, novel way to develop a treatment.”
The study, published in the Journal of Experimental Medicine, found the cells are triggered as tau accumulates – forming the crucial link between protein clumping and brain damage.
Eliminating them dramatically reduced tau in the mice – protecting them against brain damage.
Suppressing microglia, may prevent or delay the onset of dementia in people, said Prof Holtzman.
The disease affects 850,000 people in the UK – with the number set to rise to 2 million by 2050. A drug that treats the cause is the ‘holy grail’ of research.
Prof Holtzman said: “Right now many people are trying to develop new therapies for Alzheimer’s disease, because the ones we have are simply not effective.
“If we could find a drug that specifically deactivates the microglia just at the beginning of the neurodegeneration phase of the disease, it would absolutely be worth evaluating in people.”
Under ordinary circumstances, tau contributes to the normal, healthy functioning of brain neuron.
In some people, though, it collects into toxic tangles that are a hallmark of Alzheimer’s and CTE, a progressive brain disease often diagnosed in boxers who have sustained repeated blows to the head.
So Prof Holtzman and lab member Dr Yang Shi analysed genetically modified mice with a mutant form of human tau that easily clumps together.
Typically, they start developing tangles at six months of age – and show signs of neurological damage by nine months.
Animals engineered to carry a variant known as APOE4 – which raises people’s risk of Alzheimer’s twelve-fold – were protected after by a drug that depleted microglia in their brains.
After being fed it for three months their brains looked essentially normal and healthy, with less evidence of harmful tau despite the presence of the mutation.
The brains of those given a placebo were severely shrunken and damaged by nine and a half months age – as long as microglia were also present.
Prof Holtzman said: “Tangles of tau form inside neurons as Alzheimer’s develops, attracting the microglia.
“The protein APOE collects inside the microglia, activating them. This causes brain damage, leading to forgetfulness and confusion.”
What is more, mice with microglia and the mutant human tau but no APOE also had minimal brain damage – and fewer signs of the dangerous tangles.
Microglia need APOE to destroy brain tissue and boost the production of tau, the researchers said.
Co author Dr Shi added: “Microglia drive neurodegeneration, probably through inflammation-induced neuronal death.
“But even if that’s the case, if you don’t have microglia, or you have microglia but they can’t be activated, harmful forms of tau do not progress to an advanced stage, and you don’t get neurological damage.”
There has not been a new dementia drug for 15 years. With an ageing population, the need to find treatments that can slow or stop disease progression is greater than ever, say Alzheimer’s charities.
