Alzheimer’s origins could begin in the womb: study

By Mark Waghorn via SWNS

The seeds of Alzheimer's are shown in the womb, according to new research.

Abnormalities in brain development lay the foundations for the memory-robbing illness, say scientists.

It opens the door to a screening program that identifies vulnerable individuals at birth.

With no cure in sight, there is an increasing focus on protective lifestyles such as staying fit and eating plenty of fish, fruit and vegetables.

Neurodegenerative diseases are generally diagnosed between the ages of 40 and 60.

But it is believed clinical signs appear several decades after the onset of decline in certain brain cell connections.

The loss may itself reflect anomalies at a molecular scale present from childhood - or even earlier, explained the French team.

Lead author Dr. Bassem Hassan, of the Paris Brain Institute, said: "We were interested in the amyloid precursor protein, or APP, which is highly expressed throughout the development of the nervous system.

"It is an exciting research target as its fragmentation produces the famous amyloid peptides, whose toxic aggregation is associated with neuronal death observed in Alzheimer's disease.

"We, therefore, suspect that APP may play a central role in the early stages of the disease."

In many species, APP is involved in various biological processes, such as repairing cerebral lesions, orchestrating cellular response after oxygen deprivation or controlling brain plasticity.

It is highly expressed during the differentiation and migration of cortical neurons. They are responsible for speech and swallowing - functions that are affected by dementia.

Formation from stem cells begins in the fetus from five weeks gestation and is almost complete by 28 weeks. It is a complex process with finely tuned mechanisms.

Co-author Dr. Khadijeh Shabani, from the same lab, said: "In humans, neurogenesis lasts particularly long compared with other species.

"Neural stem cells remain in a progenitor state for an extended period. Only later do they differentiate into glial cells, astrocytes, or oligodendrocytes that will form the architecture of the brain and spinal cord."

Until now, researchers did not know how this balance between stem cell proliferation and differentiation into several cell types was regulated.

Above all, they ignored whether the exceptionally long timespan of human neurogenesis could pave the way for neurodegenerative diseases.

Trials of Alzheimer's drugs have failed to date because they are prescribed too late, once the disease has taken hold.

The study, published in the journal Scientific Reports, opens the door to developing medications that target APP in middle age - or even earlier.

To track expression during human brain development, the researchers used cell sequencing data obtained from the fetus at ten weeks and then 18 weeks gestation.

They observed the protein was first expressed in six cell types, then, a few weeks later, in no less than 16.

They then used gene editing to produce neural stem cells in which APP was not expressed - comparing these modified cells with those obtained from fetuses.

Dr. Shabano said: "This comparison provided us with valuable data.

"We observed that in the absence of APP, neural stem cells produced many more neurons, more rapidly, and were less inclined to proliferate in the progenitor cell state."

Specifically, APP was involved in two fined-tuned genetic mechanisms - one chemical pathway which controls stem cell proliferation and another which triggers the production of new neurons.

By acting on these two levers, APP is able to regulate the timing of neurogenesis.

Analyses showed loss of APP strongly accelerates brain neurogenesis in humans, but not in rodents.

Dr. Hassan said: "In mouse models, neurogenesis is already very fast - too fast for APP deprivation to accelerate it further.

"We can imagine the regulatory role of this protein is negligible in mice, while it is essential in the neurodevelopment of our species.

"To acquire its final form, our brain needs to generate huge quantities of neurons over a very long period and according to a definite plan.

"APP-related abnormalities could cause premature neurogenesis and significant cellular stress, the consequences of which would be observable later.

"Moreover, the brain regions in which early signs of Alzheimer's disease appear also take the longest to mature during childhood and adolescence."

The timing of human neurogenesis could be directly linked to the mechanisms of neurodegeneration.

The number of dementia cases worldwide will triple to more than 150 million by 2050 because of aging populations.

A therapy that targets the cause is a 'holy grail' of medical research. Further studies will be needed to confirm APP plays a central role.

Dr. Hassan added: "In which case, we could consider these disturbances lead to the formation of a brain that functions normally at birth but is particularly vulnerable to certain biological events such as inflammation, excitotoxicity or somatic mutations - and certain environmental factors such as a poor diet, lack of sleep, infections, etc.

"Over time, these different stresses could lead to neurodegeneration - a phenomenon specific to the human species and made particularly visible by the increase in life expectancy."