Amyloid-ß impairs mitochondrial dynamics and autophagy in Alzheimer's disease experimental models.

The most accepted hypothesis in Alzheimer's disease (AD) is the amyloid cascade which establishes that Aß accumulation may induce the disease development. This accumulation may occur years before the clinical symptoms but it has not been elucidated if this accumulation is the cause or the consequence of AD. It is however, clear that Aß accumulation exerts toxic effects in the cerebral cells. It is important then to investigate all possible associated events that may help to design new therapeutic strategies to defeat or ameliorate the symptoms in AD. Alterations in the mitochondrial physiology have been found in AD but it is not still clear if they could be an early event in the disease progression associated to amyloidosis or other conditions. Using APP/PS1 mice, our results support published evidence and show imbalances in the mitochondrial dynamics in the cerebral cortex and hippocampus of these mice representing very early events in the disease progression. We demonstrate in cellular models that these imbalances are consequence of Aß accumulation that ultimately induce increased mitophagy, a mechanism which selectively removes damaged mitochondria by autophagy. Along with increased mitophagy, we also found that Aß independently increases autophagy in APP/PS1 mice. Therefore, mitochondrial dysfunction could be an early feature in AD, associated with amyloid overload.

Annexin A5 prevents amyloid-ß-induced toxicity in choroid plexus: implication for Alzheimer's disease.

In Alzheimer's disease (AD) amyloid-ß (Aß) deposits may cause impairments in choroid plexus, a specialised brain structure which forms the blood-cerebrospinal fluid (CSF) barrier. We previously carried out a mass proteomic-based study in choroid plexus from AD patients and we found several differentially regulated proteins compared with healthy subjects. One of these proteins, annexin A5, was previously demonstrated implicated in blocking Aß-induced cytotoxicity in neuronal cell cultures. Here, we investigated the effects of annexin A5 on Aß toxicity in choroid plexus. We used choroid plexus tissue samples and CSF from mild cognitive impairment (MCI) and AD patients to analyse Aß accumulation, cell death and annexin A5 levels compared with control subjects. Choroid plexus cell cultures from rats were used to analyse annexin A5 effects on Aß-induced cytotoxicity. AD choroid plexus exhibited progressive reduction of annexin A5 levels along with progressive increased Aß accumulation and cell death as disease stage was higher. On the other hand, annexin A5 levels in CSF from patients were found progressively increased as the disease stage increased in severity. In choroid plexus primary cultures, Aß administration reduced endogenous annexin A5 levels in a time-course dependent manner and simultaneously increased annexin A5 levels in extracellular medium. Annexin A5 addition to choroid plexus cell cultures restored the Aß-induced impairments on autophagy flux and apoptosis in a calcium-dependent manner. We propose that annexin A5 would exert a protective role in choroid plexus and this protection is lost as Aß accumulates with the disease progression. Then, brain protection against further toxic insults would be jeopardised.

Endothelial-specific deficiency of megalin in the brain protects mice against high-fat diet challenge.

BACKGROUND: The increasing risk of obesity and diabetes among other metabolic disorders are the consequence of shifts in dietary patterns with high caloric-content food intake. We previously reported that megalin regulates energy homeostasis using blood-brain barrier (BBB) endothelial megalin-deficient (EMD) mice, since these animals developed obesity and metabolic syndrome upon normal chow diet administration. Obesity in mid-life appears to be related to greater dementia risk and represents an increasing global health issue. We demonstrated that EMD phenotype induced impaired learning ability and recognition memory, neurodegeneration, neuroinflammation, reduced neurogenesis, and mitochondrial deregulation associated with higher mitochondrial mass in cortical tissues. METHODS: EMD mice were subjected to normal chow and high-fat diet (HFD) for 14 weeks and metabolic changes were evaluated. RESULTS: Surprisingly, BBB megalin deficiency protected against HFD-induced obesity improving glucose tolerance and preventing hepatic steatosis. Compared to wild type (wt), the brain cortex in EMD mice showed increased levels of the mitochondrial biogenesis regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2), a thermogenic protein involved in the regulation of energy metabolism. This agreed with the previously found increased mitochondrial mass in the transgenic mice. Upon HFD challenge, we demonstrated these two proteins were found elevated in wt mice but reported no changes over the already increased levels in EMD animals. CONCLUSION: We propose a protective role for megalin on diet-induce obesity, suggesting this could be related to metabolic disturbances found in dementia through brain endocrine system communications.

Amyloid ß-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition.

BACKGROUND: The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood-brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid ß (Aß) overload. METHODS: We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice. After 5 weeks of S14 treatment, we evaluated cognitive functions and brain tissues. We also assessed the effects of S14 on the Aß-treated human neuroblastome SH-SY5Y cell line. RESULTS: Targeting the cyclic adenosine monophosphate (cAMP)/cAMP-response element binding protein (CREB) pathway, S14 rescued cognitive decline by improving hippocampal neurogenesis in APP/PS1 transgenic mice. Additionally, S14 treatment reverted the Aß-induced reduction in mitochondrial mass in APP/PS1 mice and in the human neuroblastoma SH-SY5Y cells co-exposed to Aß. The restoration of the mitochondrial mass was found to be a dual effect of S14: a rescue of the mitochondrial biogenesis formerly slowed down by Aß overload, and a reduction in the Aß-increased mitochondrial clearance mechanism of mitophagy. CONCLUSIONS: Here, we show new therapeutic effects of the PDE7 inhibitor, confirming S14 as a potential therapeutic drug for AD.