The role of mitochondria in amyloid βpeptide (Aβ)‐induced cytotoxicity is unclear. We therefore exposed NT2 cells, a clonal human teratocarcinoma cell line capable of differentiation into terminal neurons, to Aβ 25–35 or to Aβ 1–42 to evaluate cell viability and altered mitochondrial function. A 24‐h incubation of native NT2 cells (ρ+ cells) with Aβ 25–35 or with Aβ 1–42 produced a dose‐dependent decline in MTT reduction. Aβ 1–42 was shown to be more toxic compared with Aβ 25–35. Aβ 25–35 toxicity was prevented or diminished by a 22‐h preincubation with antioxidants (vitamin E, melatonin, and idebenone), as well as by simultaneous incubation with GSH or the nicotinic receptor agonist nicotine. Aβ 25–35 exposure was also associated with (1) inhibition of mitochondrial respiratory chain complexes (I, NADH‐ubiquinone oxidoreductase; II/III, succinate‐cytochrome c oxidoreductase; and IV, cytochrome c oxidase), (2) ATP depletion, and (3) reduction of the mitochondrial membrane potential. In contrast, NT2 cells rendered incapable of oxidative phosphorylation via depletion of their mitochondrial DNA (ρ0 cells) were unaffected by exposure to Aβ 25–35 or Aβ 1–42. These data indicate that Aβ can disrupt mitochondrial function and that such disruption causes oxidative stress. It is further suggested that a functional mitochondrial respiratory chain is required for Aβ toxicity.

No abstract

Mutations in leucine-rich repeat kinase 2 ( lrrk2) gene cause inherited Parkinson's disease (PD), and common variants in lrrk2 are a risk factor for sporadic PD. The neuropathology associated with LRRK2-linked PD is extremely pleomorphic involving inclusions of α-synuclein (SNCA), tau or neither, therefore suggesting that LRRK2 may be central in the pathogenic pathways of PD. This large protein localizes in the cytosol, as well as, in specific membrane domains, including mitochondria and autophagosomes and interacts with a wide range of proteins such as SNCA, tau, α- and β-tubulin. For this reason LRRK2 has been associated with a variety of cellular functions, including autophagy, mitochondrial function/dynamics and microtubule/cytoskeletal dynamics. LRRK2 has been shown to interact with microtubules as well as with mitochondria interfering with their network and dynamics. Moreover, LRRK2 knock-out or mutations affect autophagic efficiency. Here, we review and discuss the literature on how LRRK2 affects mitochondrial function, autophagy, and microtubule dynamics and how this is implicated in the PD etiology.

Novel tacrine–cinnamate and –cinnamylidenacetate as multitargeted compounds in view of AD drugs: anti-AChE and anti-oxidant activity as well as cell neuroprotection.

Recent studies have revealed that endoplasmic reticulum (ER) disturbance is involved in the pathophysiology of neurodegenerative disorders, contributing to the activation of the ER stress-mediated apoptotic pathway. Therefore, we investigated here the molecular mechanisms underlying the ER-mitochondria axis, focusing on calcium as a potential mediator of cell death signals. Using NT2 cells treated with brefeldin A or tunicamycin, we observed that ER stress induces changes in the mitochondrial function, impairing mitochondrial membrane potential and distressing mitochondrial respiratory chain complex Moreover, stress stimuli at ER level evoked calcium fluxes between ER and mitochondria. Under these conditions, ER stress activated the unfolded protein response by an overexpression of GRP78, and also caspase-4 and-2, both involved upstream of caspase-9. Our findings show that ER and mitochondria interconnection plays a prominent role in the induction of neuronal cell death under particular stress circumstances. [BMB reports 2009; 42(11): 719-724]