Apolipoprotein E-mimetics inhibit neurodegeneration and restore cognitive functions in a transgenic Drosophila model of Alzheimer's disease.

BACKGROUND: Mutations of the amyloid precursor protein gene (APP) are found in familial forms of Alzheimer's disease (AD) and some lead to the elevated production of amyloid-beta-protein (Abeta). While Abeta has been implicated in the causation of AD, the exact role played by Abeta and its APP precursor are still unclear. PRINCIPAL FINDINGS: In our study, Drosophila melanogaster transgenics were established as a model to analyze AD-like pathology caused by APP overexpression. We demonstrated that age related changes in the levels and pattern of synaptic proteins accompanied progressive neurodegeneration and impairment of cognitive functions in APP transgenic flies, but that these changes may be independent from the generation of Abeta. Using novel peptide mimetics of Apolipoprotein-E, COG112 or COG133 proved to be neuroprotective and significantly improved the learning and memory of APP transgenic flies. CONCLUSIONS: The development of neurodegeneration and cognitive deficits was corrected by injections of COG112 or COG133, novel mimetics of apolipoprotein-E (apoE) with neuroprotective activities.

G2019S LRRK2 mutation in familial and sporadic Parkinson's disease in Russia.

Among mutations associated with autosomal dominant and sporadic Parkinson's disease (PD) the G2019S substitution in the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequently identified. To estimate its frequency in Russia, we analyzed 208 patients with PD from the Northwestern region of Russia. Of these, 51 patients were probands from families with PD compatible with autosomal dominant inheritance. The control group represented 161 subjects without neurological disorders settled in the same region. The frequency of the G2019S mutation was greater in familial PD (2 [3.9%] of 51) than in sporadic PD (1 [0.6%] of 157). In addition, this mutation was found in the proband's father, who also had PD, in 1 PD family, and in 1 carrier without signs of PD at age 40 in another PD family. All carriers were heterozygous for the G2019S mutation and reported the Ashkenazi Jewish origin. The mutation was not found in the control group.

Selection of peptides binding to the amyloid b-protein reveals potential inhibitors of amyloid formation.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid plaques, cerebrovascular amyloid deposits, intracellular neurofibrillary tangles, and neuronal loss. Amyloid deposits are composed of insoluble fibers of a 39-43 amino acid peptide named the amyloid beta-protein (A beta). Neuropathological and genetic studies provide strong evidence of a key role for A beta amyloidosis in the pathogenesis of AD. Therefore, an obvious pharmacological target for treatment of AD is the inhibition of amyloid growth and/or inhibition of amyloid function. We took an unbiased approach to generate new inhibitors of amyloid formation by screening a FliTrx combinatorial peptide library for A beta binding peptides and identified four groups of peptides with different A beta binding motifs. In addition, we designed and examined peptides mimicking the A beta binding domain of transthyretin (TTR). Our results showed that A beta binding peptides selected from FliTrx peptide library and from TTR-peptide analogs are capable of inhibiting A beta aggregation and A beta deposition in vitro. These properties demonstrate that binding of selected peptides to the amyloid beta-protein may provide potent therapeutic compounds for the treatment AD.

Amyloidogenic and anti-amyloidogenic properties of recombinant transthyretin variants.

Most transthyretin (TTR) mutations lead to TTR amyloid depositions in patients with familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy. However, though an amyloidogenic protein itself, TTR inhibits aggregation of Alzheimer's amyloid beta protein (A beta) in vitro and in vivo. The pathogenic relationship between two amyloidogenic processes remains unclear. To understand how TTR mutations influence the ability of TTR to inhibit A beta amyloidosis, forty-seven recombinant TTR variants were produced and analyzed. We showed that all recombinant proteins formed tetramers and were functional in thyroxine binding. Acid denaturation at pH 3.8 resulted in aggregation and fibril formation of all TTR variants. However, only TTR G42 and TTR P55 formed fibrils at pH 6.8. Most TTR variants bound to A beta and inhibited A beta aggregation in vitro. TTR variants S64, A71, Q89, V107, H114 and I122 revealed decreased binding to A beta and decreased inhibition of A beta aggregation. Only TTR G42 and TTR P55 completely failed to bind A beta and to inhibit A beta aggregation. We suggest that TTR variants characterized by decreased binding to A beta or by decreased inhibition of A beta aggregation in vitro may contribute to A beta amyloid formation in vivo. These TTR variants might be important targets for epidemiological studies in Alzheimer's disease.

PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations.

Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by gamma-secretase inhibitors. Pharmacological and genetic evidence indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association. Furthermore, conditions that inhibit this association prevent the PS1-induced PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1 promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at AD-related residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.