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How a stressful life can contribute to the development of Alzheimer’s disease

01.11.2007

Research about to published in the journal Molecular Psychiatry, resulting from a collaboration between scientists in Germany, Portugal and the UK, suggests that stress contribute directly to the development of Alzheimer’s disease (AD).

According to the results now published, stress induces the production of amyloid beta (Aâ) peptide – the molecule associated with the neural plaques characteristic of the disease – and also makes neurons more vulnerable to Aâ toxicity. Administration of glucocorticoids (GC) - the production of which is the first physiological response to stress – was shown to have the same effect, confirming the role of stress in AD. This last result is particularly important as GC are used to treat Alzheimer’s patients and according to this research instead of helping they might be, instead, contributing to the disease.

Alzheimer’s disease is part of a group of illnesses called amyloidoses, which result from protein failure to fold and work properly (proteins’ shape is directly related to their functionality) leading, instead, to their accumulation as toxic insoluble plaques (or amyloids). In Alzheimer’s the misfolded protein is called Aâ and is found as insoluble plaques in the diseased neurons of patients.

It is known that AD patients can have higher anxiety and GC levels than those found on normal individuals and, in rodent models of AD, it has been found that stress can exacerbate the disease. Furthermore, high stressful conditions leads to cognitive impairments very similar to those found in AD patients. These observations have led researchers C Catania, N Sousa, OFX Almeida and colleagues in Germany, Portugal and the UK to wonder if there could be a causal relationship between stress and AD.

In order to investigate this possible link the researchers tested middle-aged rats in different stressful situations looking into Aâ peptide (and also another molecule called C99) levels in the hippocampus and the prefrontal cortex areas of the rats’ brain.

In fact, the first signs of AD do not correlate with the insoluble plaques of Aâ protein found in the diseased brain, but instead, with the levels of soluble Aâ peptide, while the hippocampus and the prefrontal cortex are the first brain areas affected in AD. Furthermore the Aâ peptide is formed from the breakdown of the amyloid precursor protein APP in a series of consecutive steps that originate a molecule called C99, which, when further degraded/cleaved, creates the Aâ peptide (APP –… – C99 – Aâ). And while Aâ peptide is well known to be neurotoxic, recent reports have indicated that C99 – besides being the precursor of Aâ - has a similar toxicity with both molecules affecting neural function and also cognitive behaviour. This has led Catania, Sousa, Almeida and colleagues to use the brain levels of both Aâ and C99 as a measure of potential neuro-damage and AD development in their experiments. Additionally, the researchers also looked into the consequences of glucocorticoids administration in order to confirm the specific effects of stress in AD, since GC secretion is the first physiological response to stress.

The team of researchers found that stressful situations or injections of GC (which mimic stress) led to an increase of both C99 and, eventually, of Aâ in both the hippocampus and the prefrontal cortex of the rats’ brain. Furthermore, rats with a history of stress were more susceptible to the effects of stress or GC administration, showing bigger increases in C99 levels. It was also observed that administration of soluble Aâ led to a similar increase in C99 in the rats’ brain, supporting results by others that have shown that Aâ can induce its own production, but also suggesting that Aâ, stress and GC induced the same biochemical responses.

Next, Catania and colleagues looked at the animals’ behaviour - as behavioural changes are the hallmark of AD - more specifically, at their learning and memory abilities, as these are the two first cognitive functions affected in the disease. They also looked into the rats’ anxiety levels since AD patients are known to be abnormally anxious.

For the analysis of spatial memory abilities, stressed and non-stressed rats were tested in a maze over 4 days while their emotional state was accessed by looking into anxiety levels, locomotion patterns and exploratory behaviour.
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Their first conclusion was that, like AD patients, rats put into stressful situations or receiving GC were much more anxious than controls. It was also shown that these rats showed had less exploratory interest than control animals. Spatial reference memory – which is involved in learning with repeated experiences, such as those experienced in the maze – was similarly impaired by stress or administration of GC or Aâ. This last result again supports the conclusion that the GC and Aâ act on DA through the same biochemical mechanism. When stress and GC were applied together, spatial reference memory impairment increased revealing a cumulative effect of the various factors.

In conclusion, Catania, Sousa, Almeida and colleagues show that stress can contribute to Alzheimer’s disease in two ways: by inducing the production of known neurotoxic molecules - C99 and Aâ that affect neural function and cognitive behaviour, but also – in the case of existing a previous history of stress – by making animals more susceptible to the C99-inducing effects of GC and Aâ.These results – if further confirmed – have important implications for the understanding of the mechanisms behind Alzheimer’s disease and its predisposing factors and, consequently, also for possible therapeutic approaches.

Catania, Sousa, Almeida and colleagues’ research elucidates the mechanism behind stress and GC direct effect on the brain, and can also be important to understand how stress-mediated diseases, such as depression, affect brain function. The research also alert to the need of investigating further the use of GC in AD therapy and calls for the importance of, when treating AD patients, access previous history of stress or GC therapy.

Piece researched and written by Catarina Amorim – Catarina.Amorim at linacre.ox.ac.uk