Inmaculada Pereda-Pérez

PTEN recruitment controls synaptic and cognitive function in Alzheimer's models

Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimers disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimers disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.

Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement

A small peptide from a neuronal cell adhesion molecule enhances synaptic plasticity in the hippocampus and results in improved cognitive performance in rats.

Long-term social isolation in the adulthood results in CA1 shrinkage and cognitive impairment.

Social isolation in adulthood is a psychosocial stressor that can result in endocrinological and behavioral alterations in different species. In rodents, controversial results have been obtained in fear conditioning after social isolation at adulthood, while neural substrates underlying these differences are largely unknown. Neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) are prominent modulators of synaptic plasticity underlying memory processes in many tasks, including fear conditioning. In this study, we used adult female Octodon degus to investigate the effects of long-term social isolation on contextual and cued fear conditioning, and the possible modulation of the synaptic levels of NCAM and PSA-NCAM in the hippocampus. After 6½ months of social isolation, adult female degus showed a normal auditory-cued fear memory, but a deficit in contextual fear memory, a hippocampal dependent task. Subsequently, we observed reduced hippocampal synaptic levels of PSA-NCAM in isolated compared to grouped-housed female degus. No significant differences were found between experimental groups in hippocampal levels of the three main isoforms of NCAM (NCAM180, NCAM140 and NCAM120). Interestingly, social isolation reduced the volume of the hippocampal CA1 subfield, without affecting the volume of the CA3 subregion or the total hippocampus. Moreover, attenuated body weight gain and reduced number of granulocytes were detected in isolated animals. Our findings indicate for the first time, that long-term social isolation of adult female animals induces a specific shrinkage of CA1 and a decrease in synaptic levels of PSA-NCAM in the hippocampus. These effects may be related to the deficit in contextual fear memory observed in isolated female degus.

Increased morning salivary cortisol levels in older adults with nonamnestic and multidomain mild cognitive impairment

Exposure to elevated glucocorticoid levels has a detrimental impact on cognitive function. In the present study, elderly individuals were classified according to their cognitive status to (i) cognitively healthy; (ii) amnestic; (iii) nonamnestic; or (iv) multidomain, with an extensive cognitive profiling. Salivary cortisol samples were taken at awakening, evening and night. We report that, compared to cognitively normal control individuals, subjects with nonamnestic or multidomain mild cognitive impairment profiles show increased salivary cortisol levels, immediately after awakening, but not in the evening or at night. Importantly, individuals with amnestic mild cognitive impairment did not show this increase in salivary cortisol levels. We also found that higher morning cortisol levels were associated with a lower global cognitive state, as well as poorer score in executive function and visuoconstructive praxes, verbal fluency, and a worse free immediate recall of items from a word list. These findings open new avenues to the use of salivary cortisol levels as a possible biomarker for nonamnestic and multidomain mild cognitive impairment in elderly subjects.

The Effect of Psychological Stress and Social Isolation on Neuroimmunoendocrine Communication

The adaptive response to physical or psychological challenges or threats involves the modulation of the three regulatory systems: the nervous, endocrine and immune systems. Correct communication between these systems is required to maintain a homeostatic balance, and to guarantee the health and survival of the individual. While the stress response is essential for survival, failure to cope with a stress can impair the function of these regulatory systems and prevent effective communication between them. Under such circumstances, the loss of homeostasis ultimately leads to the development of pathologies that can compromise survival. Social species live in groups, the maintenance of which ensures the survival of the individual by providing protection from environmental threats. However, the disruption of social bonds in such species constitutes a potent emotional stress. Thus, social isolation is considered a risk factor for morbidity and mortality. The response to isolation or loneliness can vary greatly between individuals due to the influence of many factors, some of which will be considered in this Review. These factors can exert a significant influence on the three regulatory systems throughout the lifespan of the organism, and they include characteristics of the stressor itself (e.g., duration), as well as those of the organism (e.g., biological age), in addition to external factors (e.g., environmental events).

Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment.

A higher anxiety state in old rats after social isolation is associated to an impairment of the immune response.

Social isolation is common in the elderly exerting negative effects on neuroimmunoendocrine communication. Nevertheless physiological responses to a stressful situation may vary according to diverse factors. This work studies the differences in the immune response of aged male rats socially isolated depending on the anxiety levels produced. Social isolation impaired certain immunological parameters, but a more anxious response to isolation was associated to global severe immunosuppression and greater oxidative state. Thus, responding anxiously to isolation may suppose a more potent risk of morbidity and mortality further than isolation and anxiety by themselves, particularly in elderly subjects.

The Characterization of Biological Rhythms in Mild Cognitive Impairment

Introduction. Patients with dementia, especially Alzheimers disease, present several circadian impairments related to an accelerated perturbation of their biological clock that is caused by the illness itself and not merely age-related. Thus, the objective of this work was to elucidate whether these circadian system alterations were already present in patients with mild cognitive impairment (MCI), as compared to healthy age-matched subjects. Methods. 40 subjects (21 patients diagnosed with MCI, 74.1 ± 1.5 y.o., and 19 healthy subjects, 71.7 ± 1.4 y.o.) were subjected to ambulatory monitoring, recording wrist skin temperature, motor activity, body position, and the integrated variable TAP (including temperature, activity, and position) for one week. Nonparametrical analyses were then applied. Results. MCI patients exhibited a significant phase advance with respect to the healthy group for the following phase markers: temperature M5 (mean ± SEM: 04:20 ± 00:21 versus 02:52 ± 00:21) and L10 (14:35 ± 00:27 versus 13:24 ± 00:16) and TAP L5 (04:18 ± 00:14 versus 02:55 ± 00:30) and M10 (14:30 ± 00:18 versus 13:28 ± 00:23). Conclusions. These results suggest that significant advances in the biological clock begin to occur in MCI patients, evidenced by an accelerated aging of the circadian clock, as compared to a healthy population of the same age.

Administration of the TrkB receptor agonist 7,8‐dihydroxyflavone prevents traumatic stress‐induced spatial memory deficits and changes in synaptic plasticity

Post‐traumatic stress disorder (PTSD) occurs after exposure to traumatic situations and it is characterized by cognitive deficits that include impaired explicit memory. The neurobiological bases of such PTSD‐associated memory alterations are yet to be elucidated and no satisfactory treatment for them exists. To address this issue, we first studied whether a single exposure of young adult rats (60 days) to immobilization on boards (IMO), a putative model of PTSD, produces long‐term behavioral effects (2–8 days) similar to those found in PTSD patients. Subsequently, we investigated whether the administration of the TrkB agonist 7,8‐dihydroxyflavone (DHF) 8 h after stress (therapeutic window) ameliorated the PTSD‐like effect of IMO and the associated changes in synaptic plasticity. A single IMO exposure induced a spatial memory impairment similar to that found in other animal models of PTSD or in PTSD patients. IMO also increased spine density and long‐term potentiation (LTP) in the CA3‐CA1 pathway. Significantly, DHF reverted both spatial memory impairment and the increase in LTP, while it produced no effect in the controls. These data provide novel insights into the possible neurobiological substrate for explicit memory impairment in PTSD patients, supporting the idea that the activation of the BDNF/TrkB pathway fulfils a protective role after severe stress. Administration of DHF in the aftermath of a traumatic experience might be relevant to prevent its long‐term consequences.