Modulation of the endoplasmic reticulum–mitochondria interface in Alzheimer’s disease and related models

Abstract

It is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer's disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation. The effect of AD pathogenesis on the ER-mitochondria interplay in the brain has so far remained unknown. Here, we studied ERmitochondria contacts in human AD brain and related AD mouse and neuronal cell models. We found uniform distribution of MAM in neurons. Phosphofurin acidic cluster sorting protein-2 and σ1 receptor, two MAM-associated proteins, were shown to be essential for neuronal survival, because siRNA knockdown resulted in degeneration. Up-regulated MAM-associated proteins were found in the AD brain and amyloid precursor protein (APP) Swe/Lon mouse model, in which up-regulation was observed before the appearance of plaques. By studying an ER-mitochondria bridging complex, inositol-1,4,5-triphosphate receptor-voltage-dependent anion channel, we revealed that nanomolar concentrations of amyloid β-peptide increased inositol-1,4,5-triphosphate receptor and voltage-dependent anion channel protein expression and elevated the number of ER-mitochondria contact points and mitochondrial calcium concentrations. Our data suggest an important role of ER-mitochondria contacts and cross-talk in AD pathology.AD mouse models | hippocampal neurons | human cortical brain tissue

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

“…Second, upregulation of SMase and the resulting increase in ceramide are known to alter the size and composition of lipid raft domains (Dinkla et al , 2012), such as MAM. Therefore, an increased localization of C99 in MAM in AD may explain the upregulation of ER–mitochondria connections and MAM functionality seen in the disease (Area‐Gomez et al , 2012; Hedskog et al , 2013). Finally, given the detrimental effect of ceramide on mitochondrial supercomplex assembly and respiratory chain activity (Zigdon et al , 2013), we conclude that its accumulation is likely to be a primary cause of mitochondrial dysfunction in AD.…”

“…Moreover, MAM functionality (Area‐Gomez et al , 2012) and ER–mitochondrial apposition (Area‐Gomez et al , 2012; Hedskog et al , 2013) are increased in AD.…”

The coming of age of the mitochondria–ER contact: a matter of thickness

“…[61][62][63] and paving the way to studies showing upregulated expression of MAM-associated proteins in human and mouse AD brains prior to the appearance of amyloid plaques. 64 Thus, altered lipid-MERC function might trigger amyloid plaques formation, which is at the core of the 'amyloid hypothesis'; in this scenario, the MAM and the amyloid hypothesis are not mutually exclusive, but place the loss of lipid homeostasis upstream of amyloid plaques deposition. Given the compelling evidence supporting the MAM hypothesis and the lack of therapies for AD patients, studies addressing this pathology as a brain metabolic disorder in lipid homeostasis are warranted.…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…Conversely, PACS-2 knockdown protects liver from overnutritioninduced steatosis and optimizes mitochondrial respiration and insulin sensitivity (Arruda et al, 2014). Aberrantly elevated PACS-2 and MAM formation are also found in neurons from Alzheimer's patients and Alzheimer's mouse models, suggesting that the deleterious consequences from abnormally strong MAM formation in this disease may also result from dysregulated PACS-2 expression (Area-Gomez et al, 2012; Hedskog et al, 2013).…”