Neuronal network controlling REM sleep.

Rapid eye movement sleep is a state characterized by concomitant occurrence of rapid eye movements, electroencephalographic activation and muscle atonia. In this review, we provide up to date knowledge on the neuronal network controlling its onset and maintenance. It is now accepted that muscle atonia during rapid eye movement sleep is due to activation of glutamatergic neurons localized in the pontine sublaterodorsal tegmental nucleus. These neurons directly project and excite glycinergic/γ-aminobutyric acid-ergic pre-motoneurons localized in the ventromedial medulla. The sublaterodorsal tegmental nucleus rapid eye movement-on neurons are inactivated during wakefulness and non-rapid eye movement by rapid eye movement-off γ-aminobutyric acid-ergic neurons localized in the ventrolateral periaqueductal grey and the adjacent dorsal deep mesencephalic reticular nucleus. Melanin-concentrating hormone and γ-aminobutyric acid-ergic rapid eye movement sleep-on neurons localized in the lateral hypothalamus would inhibit these rapid eye movement sleep-off neurons initiating the state. Finally, the activation of a few limbic cortical structures during rapid eye movement sleep by the claustrum and the supramammillary nucleus as well as that of the basolateral amygdala would be involved in the function(s) of rapid eye movement sleep. In summary, rapid eye movement sleep is generated by a brainstem generator controlled by forebrain structures involved in autonomic control.

The amyloid precursor protein and its derived fragments concomitantly contribute to the alterations of mitochondrial transport machinery in Alzheimer's disease.

Mitochondria dysfunctions and mitophagy failure have been associated with several Alzheimer's disease (AD) related molecular actors including amyloid beta (Aß) and recently the amyloid precursor protein-C terminal fragments (APP-CTFs). The efficacy of the mitophagy process in neurons relies on regulated mitochondrial transport along axons involving a complex molecular machinery. The contribution of the amyloid precursor protein (APP) and its derived fragments to the mitochondrial transport machinery alterations in AD have not been investigated before. We report herein a change of the expression of mitochondrial transport proteins (SNPH and Miro1), motor adapters (TRANK1 and TRAK2), and components of the dynein and kinesin motors (i.e., IC1,2 and Kif5 (A, B, C) isoforms) by endogenous APP and by overexpression of APP carrying the familial Swedish mutation (APPswe). We show that APP-CTFs and Aß concomitantly regulate the expression of a set of transport proteins as demonstrated in APPswe cells treated with ß- and γ-secretase inhibitors and in cells Knock-down for presenilin 1 and 2. We further report the impact of APP-CTFs on the expression of transport proteins in AAV-injected C99 mice brains. Our data also indicate that both Aß oligomers (Aßo) and APP-CTFs impair the colocalization of mitochondria and transport proteins. This has been demonstrated in differentiated SH-SY5Y naive cells treated with Aßo and in differentiated SH-SY5Y and murine primary neurons expressing APPswe and treated with the γ-secretase inhibitor. Importantly, we uncover that the expression of a set of transport proteins is modulated in a disease-dependent manner in 3xTgAD mice and in human sporadic AD brains. This study highlights molecular mechanisms underlying mitochondrial transport defects in AD that likely contribute to mitophagy failure and disease progression.