Laetitia El Haylani

Amyloid precursor protein controls cholesterol turnover needed for neuronal activity.

Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full‐length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG‐CoA reductase (HMGCR)‐mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co‐immunoprecipitated and co‐localized in the Golgi. This interaction prevented Site‐2 protease‐mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24‐hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity.

Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimer's disease

Tau alterations are now considered an executor of neuronal demise and cognitive dysfunction in Alzheimers disease (AD). Mouse models combining amyloidosis and tauopathy and their parental counterparts are important tools to further investigate the interplay of abnormal amyloid‐β (Aβ) and Tau species in pathogenesis, synaptic and neuronal dysfunction, and cognitive decline. Here, we crossed APP/PS1 mice with 5 early‐onset familial AD mutations (5xFAD) and TauP301S (PS19) transgenic mice, denoted F+/T+ mice, and phenotypically compared them to their respective parental strains, denoted F+/T– and F–/T+ respectively, as controls. We found dramatically aggravated tauopathy (~10‐fold) in F+/T+ mice compared to the parental F–/T+ mice. In contrast, amyloidosis was unaltered compared to the parental F+/T– mice. Tauopathy was invariably and very robustly aggravated in hippocampal and cortical brain regions. Most important, F+/T+ displayed aggravated cognitive deficits in a hippocampus‐dependent spatial navigation task, compared to the parental F+/T– strain, while parental F–/T+ mice did not display cognitive impairment. Basal synaptic transmission was impaired in F+/T+ mice compared to nontransgenic mice and the parental strains (≥40%). Finally, F+/T+ mice displayed a significant hippocampal atrophy (~20%) compared to nontransgenic mice, in contrast to the parental strains. Our data indicate for the first time that pathological Aβ species (or APP/PS1) induced changes in Tau contribute to cognitive deficits correlating with synaptic deficits and hippocampal atrophy in an AD model. Our data lend support to the amyloid cascade hypothesis with a role of pathological Aβ species as initiator and pathological Tau species as executor.—Stancu, I.‐C., Ris, L., Vasconcelos, B., Marinangeli, C., Goeminne, L., Laporte, V., Haylani, L. E., Couturier, J., Schakman, O., Gailly, P., Pierrot, N., Kienlen‐Campard, P., Octave, J.‐N., Dewachter, I. Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimers disease. FASEB J. 28, 2620–2631 (2014). www.fasebj.org

Conformational Changes Induced by the A21G Flemish Mutation in the Amyloid Precursor Protein Lead to Increased Aβ Production

Proteolysis of the β C-terminal fragment (β-CTF) of the amyloid precursor protein generates the Aβ peptides associated with Alzheimers disease. Familial mutations in the β-CTF, such as the A21G Flemish mutation, can increase Aβ secretion. We establish how the Flemish mutation alters the structure of C55, the first 55 residues of the β-CTF, using FTIR and solid-state NMR spectroscopy. We show that the A21G mutation reduces β sheet structure of C55 from Leu17 to Ala21, an inhibitory region near the site of the mutation, and increases α-helical structure from Gly25 to Gly29, in a region near the membrane surface and thought to interact with cholesterol. Cholesterol also increases Aβ peptide secretion, and we show that the incorporation of cholesterol into model membranes enhances the structural changes induced by the Flemish mutant, suggesting a common link between familial mutations and the cellular environment.

Analysis by a highly sensitive split luciferase assay of the regions involved in APP dimerization and its impact on processing

Alzheimers disease (AD) is a neurodegenerative disease that causes progressive loss of cognitive functions, leading to dementia. Two types of lesions are found in AD brains: neurofibrillary tangles and senile plaques. The latter are composed mainly of the β‐amyloid peptide (Aβ) generated by amyloidogenic processing of the amyloid precursor protein (APP). Several studies have suggested that dimerization of APP is closely linked to Aβ production. Nevertheless, the mechanisms controlling APP dimerization and their role in APP function are not known. Here we used a new luciferase complementation assay to analyze APP dimerization and unravel the involvement of its three major domains: the ectodomain, the transmembrane domain and the intracellular domain. Our results indicate that within cells full‐length APP dimerizes more than its α and β C‐terminal fragments, confirming the pivotal role of the ectodomain in this process. Dimerization of the APP transmembrane (TM) domain has been reported to regulate processing at the γ‐cleavage site. We show that both non‐familial and familial AD mutations in the TM GXXXG motifs strongly modulate Aβ production, but do not consistently change dimerization of the C‐terminal fragments. Finally, we found for the first time that removal of intracellular domain strongly increases APP dimerization. Increased APP dimerization is linked to increased non‐amyloidogenic processing.