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The most accepted hypothesis in Alzheimer's disease (AD) is the amyloid cascade which establishes that Aβ 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 Aβ 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 Aβ accumulation that ultimately induce increased mitophagy, a mechanism which selectively removes damaged mitochondria by autophagy. Along with increased mitophagy, we also found that Aβ independently increases autophagy in APP/PS1 mice. Therefore, mitochondrial dysfunction could be an early feature in AD, associated with amyloid overload. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD) amyloid-β (Aβ) 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 Aβ-induced cytotoxicity in neuronal cell cultures. Here, we investigated the effects of annexin A5 on Aβ toxicity in choroid plexus. We used choroid plexus tissue samples and CSF from mild cognitive impairment (MCI) and AD patients to analyse Aβ 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 Aβ-induced cytotoxicity. AD choroid plexus exhibited progressive reduction of annexin A5 levels along with progressive increased Aβ 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, Aβ 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 Aβ-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 Aβ accumulates with the disease progression. Then, brain protection against further toxic insults would be jeopardised. [ABSTRACT FROM AUTHOR]

In addition FW was supported by grants from ISCIII-CIBERNED (CB06/05/0067) and I+D+i-RETOS- RTI2018-096303-B." now reads: "This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects "PI18/00118", "PI21/00183" and "CP20/00007" and co-funded by the European Union, Comunidad de Madrid (S2017/BMD-3700; NEUROMETAB-CM), and CIBERNED (CB07/502). Correction to: I Scientifc Reports i , https://doi.org/10.1038/s41598-022-13683-3, published online 16 June 2022 The Funding section in the original version of this Article was incomplete. Author Correction: Amyloid- impairs mitochondrial dynamics and autophagy in Alzheimer's disease experimental models. [Extracted from the article]