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Alzheimer's disease (AD) is a complex degenerative disorder of the brain, associated with a progressive cognitive decline. Age is the main risk factor with almost half of the population above 90 years affected by this pathology. AD and brain aging share common molecular changes, so it has been hypothesized that AD could be a form of accelerated brain aging. In this context, senescenceassociated mechanisms could be a valuable target of investigation both to analyze the causes of this disease and to define therapeutic strategies. Senescent phenotypes of glia and neurons, as well as of peripheral cells, have been described in AD. Much evidence indicate that vascular impairment is a fundamental contributor to AD pathology and platelets are generally considered a key element because they represent the link between amyloid-β (Aβ) deposition, peripheral inflammation and endothelial senescence. Both activated and senescent platelets are a source of Aβ, in addition activated platelets secrete many proinflammatory mediators that could contribute to increased peripheral inflammation and endothelial senescence. Treatments aimed to target peripheral endothelial senescence include antioxidants and some substances, such as aspirin, that modulate platelet aggregation and inflammatory response. Heparin has been proposed as a treatment for senile dementia and exhibits anti-inflammatory action as well as inhibitory effects on Aβ assembly. Identifying peripheral targets for AD treatments could also result advantageous as it would be possible to monitor directly their efficacy. Nevertheless more research is needed to clarify all the different aspects and interactions of blood cells, vascular cells and their secretory products.

Aging is associated with a gradual decline in cognitive function, and more dramatic cognitive impairments occur in patients affected by Alzheimer’s disease (AD). Studies performed in the last two decades in aged animals and in animal models of AD have revealed that deterioration of cognitive performances is associated with significant changes in synaptic plasticity. In particular, electrophysiological studies have well documented that alterations in long-term declarative memory, extremely vulnerable to age and neurodegenerative diseases, are linked with deficits in induction and maintenance of long-term potentiation of synaptic transmission (LTP) in the hippocampus and in other temporal lobe regions involved in this form of memory. Interestingly, we have found that long-term depression of synaptic transmission (LTD) in the perirhinal cortex, a cellular correlate of visual recognition memory formation, is impaired very early (at three months of age) in a mouse transgenic model of AD. Moreover, recent morphological studies performed in aged animals have revealed a clear-cut correlation between the quality of memory performance and the extent of morphologic changes (remodeling) in synaptic contacts occurring during memory consolidation. Nutritional studies performed in aged animals have documented the effect of different diets on synaptic plasticity or morphology; interestingly, some diet supplements were found to reverse age-induced deficits in LTP or alterations in synaptic morphology.

The Tg2576 Alzheimer’s disease (AD) mouse line shows a marked increase in amyloid-β (Aβ) 1–40 and Aβ1–42 in the plasma and brain by 3–5 months of age, decrease in spine density in the dentate gyrus at 4 months, decline in long-term potentiation of synaptic transmission in the dentate gyrus associated with impairment in contextual fear conditioning by 5 months, and plaque deposition in brain starting at 8 months. Visual recognition memory is seriously impaired in patients in the early stages of AD. The perirhinal cortex (Prh), a multimodal associative cortex of the temporal lobe, is critically involved in this form of memory; long-term depression of synaptic transmission (LTD) in this cortical region is regarded as its cellular correlate. The present work was aimed at evaluating if LTD in Prh of Tg2576 mice is already compromised at 3 months of age. Field excitatory post-synaptic potentials evoked by afferent pathways stimulation were recorded in layer II/III of Prh in horizontal brain slices obtained from 3 month old Tg2576 mice and littermate controls. We found that a single train of 3000 pulses delivered at 5 Hz induced LTD in slices from control mice, but not in those from Tg2576 mice. This result is consistent with the early visual recognition impairment observed in AD patients, and is particularly interesting because no changes in synaptic plasticity have previously been found so early in this transgenic line.

Alterations of long-term declarative memory formation occur to different degrees among individuals during normal aging, but the genetic basis for such differences are not yet fully understood. Aim of the present study was the identification of genes differently expressed in the hippocampus of aged (26-27 month old) rats showing diverse cognitive performance in a single trial inhibitory avoidance (IA) task. IA is a hippocampal-dependent aversive learning, based on contextual fear conditioning. The behavioural paradigm consisted of a training phase in which animals, placed individually in the light compartment of a shock avoidance apparatus, learned to avoid the dark compartment by the delivery of a single, inescapable foot shock (0.6 mA, 2 s) when they accessed it. Rats were tested 3 and 6 hours after the training. According to the performance displayed in the tests, animals were divided into two groups: i) good responders (GR), which obtained retention times above 100s in both tests, and ii) bad responders (BR), which obtained retention times below 100s in both tests. Immediately after the last test, rats were sacrificed, hippocampi were excised and total RNA was extracted. Microarray analysis was performed to identify genes with decreased or increased expression in GR compared to BR rats by using a commercially available chip containing 9715 oligos. We found that the transcription of 43 genes was significantly increased in GR in comparison with BR, including genes functionally linked to signal transduction (e.g. rho family GTPase and dynamin binding protein), translation (e.g. ribosomal protein S6, 60s ribosomal protein L12 and mitochondrial ribosomal protein L41), cell growth and differentiation (e.g. trpc6 and NEL-like 2) energy metabolism (e.g. cytochrome c oxidase subunit VIIb and succinate dehydrogenase 1b) and nucleic acid processing (e.g. U6 small nuclear RNA associated and DEAD box 1). In addition, 18 genes were significantly down-regulated in GR, including genes functionally linked to transcription (e.g. sirtuin 5), apoptosis (e.g. cytochrome c somatic), cell growth and differentiation (e.g. cytidine 5’-triphosphate synthase) and protein transport (e.g. autophagy-related 4B). Present results may provide insight into the mechanisms by which long-term declarative memory formation is maintained in the elderly, and may contribute to the identification of novel targets that can be addressed to ameliorate memory performances.

Impairment of energy metabolism and increase of free radicals production play a major role in agerelated apoptotic loss of cardiomyocites. Since recent reports have shown that ketone bodies increase cardiac metabolic efficiency and exert cardio-protective antioxidant effects, we investigated the consequences of a medium chain triglycerides ketogenic diet (MCT-KD) on the aging heart of late-adult (19 month-old) rats. After 8-week MCT-KD feeding, the activity of succinic dehydrogenase (SDH) was cytochemically evidenced in cardiomyocites by the copper ferrocyanide method. Young (5 month-old), age-matched (19 month-old) and old (27 month-old) animals fed with a standard chow were sed as controls. The overall area of the precipitates due to SDH activity (PA) and the area of the SDH-positive mitochondria (MA) were measured. The percent ratios MA/total myocardial tissue area (MA/TA) and PA/MA were the parameters taken into account. We found that both parameters were significantly higher in MCT-KD fed rats vs. age-matched and old controls; PA/MA was significantly higher in young controls vs. late-adult MCT-KD fed and control animals, and both parameters were significantly higher in young vs. old controls. These data indicate that 8-week MCT-KD administration partially recovers the age-related decrease of SDH activity and increases the myocardial area occupied by metabolically active mitochondria. SDH is one of the most reliable markers of the mitochondrial capability to provide adequate amount of ATP, as it is part of both the Krebs cycle and the respiratory chain. Moreover, because of its unique redox properties, SDH provides a major contribution to the reduction of the ubiquinone pool, important antioxidant reservoir in the inner membrane of the organelles. Therefore, these findings suggest that MCT-KD may improve cardiac energetic efficiency, confirming and extending previous results obtained in the working perfused rat myocardium. The use of this diet might counteract typical alterations of the aging heart, which play a primary role in apoptotic-triggered myocardial atrophy.

Rats show spontaneous preference for exploring novel rather than familiar objects. Thus, exploratory activity can be used to evaluate recognition memory. To date, the spontaneous novelty-preference test of object recognition has been used to study long-term recognition memory formation in adult rats (Mumby et al., 2002 Behav Brain Res 132:215-26), but not in aged rats. In the present study we used this behavioral test with 25-27 month-old Wistar rats (n=9), but we found that it was not able to elicit recognition memory. Thus, we developed a new experimental protocol and we tested a second group of rats of the same age (n=18). Each animal received 5 training sessions (1 per day on days 1 and 2, and 1 on day 3) lasting 5 min in a small box (48x26,5x21 cm) containing two identical plastic cubes (8 cm high). We found that the time spent in exploring this pair of objects significantly (P