The mechanism of neurodegeneration caused by beta-amyloid in Alzheimer disease is controversial. Neuronal toxicity is exerted mostly by various species of soluble beta-amyloid oligomers that differ in their N- and C-terminal domains. However, abundant accumulation of beta-amyloid also occurs in the brains of cognitively normal elderly people, in the absence of obvious neuronal dysfunction. We postulated that neuronal toxicity depends on the molecular composition, rather than the amount, of the soluble beta-amyloid oligomers. Here we show that soluble beta-amyloid aggregates that accumulate in Alzheimer disease are different from those of normal aging in regard to the composition as well as the aggregation and toxicity properties.

SUMMARY Recent studies indicated that sortilin-related receptor 1 (SORL1) is a risk gene for late-onset Alzheimer9s disease (AD), although its role in the aetiology and/or progression of this disorder is not fully understood. Here, we report the finding of a non-coding (nc) RNA (hereafter referred to as 51A) that maps in antisense configuration to intron 1 of the SORL1 gene. 51A expression drives a splicing shift of SORL1 from the synthesis of the canonical long protein variant A to an alternatively spliced protein form. This process, resulting in a decreased synthesis of SORL1 variant A, is associated with impaired processing of amyloid precursor protein (APP), leading to increased Aβ formation. Interestingly, we found that 51A is expressed in human brains, being frequently upregulated in cerebral cortices from individuals with Alzheimer9s disease. Altogether, these findings document a novel ncRNA-dependent regulatory pathway that might have relevant implications in neurodegeneration.

Background and Purpose: Palmitoylethanolamide (PEA) is an endogenous fatty acid amide displaying anti‐inflammatory and analgesic actions. To investigate the molecular mechanism responsible for these effects, the ability of PEA and of pain‐inducing stimuli such as capsaicin (CAP) or bradykinin (BK) to influence intracellular calcium concentrations ([Ca²⁺]_i) in peripheral sensory neurons, has been assessed in the present study. The potential involvement of the transcription factor PPARα and of TRPV1 channels in PEA‐induced effects was also studied.Experimental Approach: [Ca²⁺]_i was evaluated by single‐cell microfluorimetry in differentiated F11 cells. Activation of TRPV1 channels was assessed by imaging and patch‐clamp techniques in CHO cells transiently‐transfected with rat TRPV1 cDNA.Key Results: In F11 cells, PEA (1–30 μM) dose‐dependently increased [Ca²⁺]_i. The TRPV1 antagonists capsazepine (1 μM) and SB‐366791 (1 μM), as well as the PPARα antagonist GW‐6471 (10 μM), inhibited PEA‐induced [Ca²⁺]_i increase; blockers of cannabinoid receptors were ineffective. PEA activated TRPV1 channels heterologously expressed in CHO cells; this effect appeared to be mediated at least in part by PPARα. When compared with CAP, PEA showed similar potency and lower efficacy, and caused stronger TRPV1 currents desensitization. Sub‐effective PEA concentrations, closer to those found in vivo, counteracted CAP‐ and BK‐induced [Ca²⁺]_i transients, as well as CAP‐induced TRPV1 activation.Conclusions and Implications: Activation of PPARα and TRPV1 channels, rather than of cannabinoid receptors, largely mediate PEA‐induced [Ca²⁺]_i transients in sensory neurons. Differential TRPV1 activation and desensitization by CAP and PEA might contribute to their distinct pharmacological profile, possibly translating into potentially relevant clinical differences.