“Conversion of Synthetic Aβ to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model” has been published in The Journal of Neuroscience. This research was supported in part by JPND through the NeuTARGETs project, which was selected for support in the 2013 call for research projects for cross-disease analysis of pathways related to neurodegenerative diseases.
Scientists have revealed that protein clumps associated with Alzheimer’s disease are also found in the brains of people who have had a head injury.
Although previous research has shown that these clumps, called amyloid plaques, are present shortly after a brain injury – this study shows the plaques are still present over a decade after the injury.
The findings may help explain why people who have suffered a serious brain injury appear to be at increased risk of dementia. Although extensive research now suggests major head injury increases dementia risk in later life, scientists do not know the biological changes that cause this effect.
In the research, published in the journal Neurology, the team studied nine patients with moderate to severe traumatic brain injuries. Many had sustained these in road traffic accidents, such as being hit by a car, between 11 months to 17 years prior to the study. The patient underwent a brain scan that used a technique that allows scientists to view amyloid plaques. These proteins are thought to be a hallmark of Alzheimer’s disease, and their formation may trigger other changes that lead to the death of brain cells.
The team also scanned the brains of healthy volunteers, and people with Alzheimer’s disease. The patients with head injury were found to have more amyloid plaques than the healthy volunteers, but fewer than those with Alzheimer’s disease.
In the head injury patients, the amyloid plaques were found to be centred mainly in two brain areas: the posterior cingulate cortex – a highly active area in the centre of the brain involved in controlling attention and memory, and the cerebellum – a region at the base of the brain involved in motor control and coordination.
In a second part of the study, the team assessed damage to so-called white matter. This is the ‘wiring’ of the brain, and enables brain cells to communicate with each other. The results showed that amyloid plaque levels in the posterior cingulate cortex were related to the amount of white matter damage, suggesting that injury to the brain’s wiring may be linked to the formation of amyloid plaques.
Source: Imperial College London
Alzheimer’s disease is characterised by two types of lesions, amyloid plaques and degenerated tau protein. Cholesterol plays an important role in the physiopathology of this disease. Two research teams have shown, in a rodent model, that overexpressing an enzyme that can eliminate excess cholesterol from the brain may have a beneficial action on the tau component of the disease, and completely correct it. This is the first time that a direct relationship has been shown between the tau component of Alzheimer’s disease and cholesterol. This work is published in Human Molecular Genetics.
The first step in this work made it possible to show that injecting a viral vector, AAV-CYP46A1, effectively corrects a mouse model of amyloid pathology of the disease, the APP23 mouse. CYP46A1 thus appears to be a therapeutic target for Alzheimer’s disease.
Conversely, in vivo inhibition of CYP46A1 in the mice, using antisense RNA molecules delivered by an AAV vector administered to the hippocampus, induces an increase in the production of Aß peptides, abnormal tau protein, neuronal death and hippocampal atrophy, leading to memory problems. Together these elements reproduce a phenotype mimicking Alzheimer’s disease.
These results demonstrate the key role of cholesterol in the disease, and confirm the relevance of CYP46A1 as a potential therapeutic target (work published in Brain on 3 July 2015).
Taken together, this work now enables the research team to propose a gene therapy approach for Alzheimer’s disease: intracerebral administration of a vector, AAV-CYP46A1, in patients with early and severe forms (1% of patients, familial forms) for whom there is no available treatment.