Vulnerability and resilience in Alzheimer’s Disease

Depriving mice of bedding and nesting materials is not extreme adversity, but it is enough to alter maternal behavior towards pups and can be used to model early life stress (ELS).

Even a short period of ELS (between post-partum days 2 to 9) reduces weight gain and increases levels of stress hormones. These changes are reversed soon after the stress ends. But there are long-term consequences: the effects of ELS can be seen in sensitivity to Alzheimer’s pathology, altered synaptic function and impaired learning of hippocampal-dependent tasks when APP/PS1 transgenic animals are six and even twelve months of age, Harmen Krugers, University of Amsterdam, The Netherlands, told the ECNP session on brain vulnerability in AD.

In a recent study, ELS was shown to have a specific effect on hippocampal neurons, altering the ratio of NMDA to AMPA receptor-mediated excitatory postsynaptic currents and probability of glutamate release.¹

Stress in the week following birth in AD animal models affects synaptic function and learning a year later

Short-term treatment with a glucocorticoid receptor antagonist in the animals’ “middle age” resulted in lower levels of amyloid-beta and prevented the ELS-induced cognitive deficits seen in untreated animals.²

The APP model also works for positive experiences

The other side of the coin is that positive early life experiences have protective effects relevant to our understanding of AD. Briefly separating a pup from its mother leads to enhanced maternal care when they are reunited. A year later, offspring who experienced enriched care do not demonstrate the impaired learning seen in control APP transgenic mice, and they have fewer amyloid plaques in the hippocampus.³ Amyloid pathology in the amygdala is not affected.

An intriguing question is whether specific learning experiences can make synapses less vulnerable to AD-related decline.

Manipulating synaptic function can improve learning and memory

It was exactly at the level of the synapse that Shira Knafo, University of the Basque Country, Bilbao, Spain, contributed to the session. As described by Dennis Selkoe some years ago, AD is essentially a condition of synaptic failure, she argued. So can we bypass amyloid and address synaptic function directly?

Her focus is on the PIP3 pathway, and evidence that use of an inhibitor of PTEN – better known in oncology as a tumor suppressor -- can rescue APP/PS1 mice from the cognitive deficits that they otherwise experience. In the APP mouse model, a novel peptide that prevents the interaction between PTEN and PDZ proteins at synapses during exposure to amyloid prevents the memory deficits that are seen when compared to control animals.⁴

People with no dementia symptoms sometimes have brains full of amyloid

The overall aim is to reveal the molecular mechanisms of amyloid-induced synaptic dysfunction and to suggest potential downstream targets.⁵ That is also the case in humans. There are brains submitted to brain banks as “normal controls” that have to be rejected because they too are full of amyloid. We are still at the start of understanding the factors responsible for such resistance.