The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD). Preventing deregulated APP processing by inhibiting amyloidogenic processing of carboxy-terminal fragments (APP-CTFs), and reducing the toxic effect of amyloid beta (Aβ) peptides remain an effective therapeutic strategy. We report the design of piperazine-containing compounds derived from chloroquine structure and evaluation of their effects on APP metabolism and ability to modulate the processing of APP-CTF and the production of Aβ peptide. Compounds which retained alkaline properties and high affinity for acidic cell compartments were the most effective. The present study demonstrates that (1) the amino side chain of chloroquine can be efficiently substituted by a bis(alkylamino)piperazine chain, (2) the quinoline nucleus can be replaced by a benzyl or a benzimidazole moiety, and (3) pharmacomodulation of the chemical structure allows the redirection of APP metabolism toward a decrease of Aβ peptide release, and increased stability of APP-CTFs and amyloid intracellular fragment. Moreover, the benzimidazole compound 29 increases APP-CTFs in vivo and shows promising activity by the oral route. Together, this family of compounds retains a lysosomotropic activity which inhibits lysosome-related Aβ production, and is likely to be beneficial for therapeutic applications in AD.

The development of Alzheimer's disease (AD) is closely connected with cholesterol metabolism. Cholesterol increases the production and deposition of amyloid-beta (A beta) peptides that result in the formation of amyloid plaques, a hallmark of the pathology. In the brain, cholesterol is synthesized in situ but cannot be degraded nor cross the blood-brain barrier. The major exportable form of brain cholesterol is 24S-hydroxycholesterol, an oxysterol generated by the neuronal cholesterol 24-hydroxylase encoded by the CYP46A1 gene. We report that the injection of adeno-associated vector (AAV) encoding CYP46A1 in the cortex and hippocampus of APP23 mice before the onset of amyloid deposits markedly reduces A beta peptides, amyloid deposits and trimeric oligomers at 12 months of age. The Morris water maze (MWM) procedure also demonstrated improvement of spatial memory at 6 months, before the onset of amyloid deposits. AAV5-wtCYP46A1 vector injection in the cortex and hippocampus of amyloid precursor protein/presenilin 1 (APP/PS) mice after the onset of amyloid deposits also reduced markedly the number of amyloid plaques in the hippo-campus, and to a less extent in the cortex, 3 months after the injection. Our data demonstrate that neuronal overexpression of CYP46A1 before or after the onset of amyloid plaques significantly reduces A beta pathology in mouse models of AD.

Alzheimer's disease (AD) is classically defined as a dual clinicopathological entity. The recent advances in use of reliable biomarkers of AD that provide in-vivo evidence of the disease has stimulated the development of new research criteria that reconceptualise the diagnosis around both a specific pattern of cognitive changes and structural/biological evidence of Alzheimer's pathology. This new diagnostic framework has stimulated debate about the definition of AD and related conditions. The potential for drugs to intercede in the pathogenic cascade of the disease adds some urgency to this debate. This paper by the International Working Group for New Research Criteria for the Diagnosis of AD aims to advance the scientific discussion by providing broader diagnostic coverage of the AD clinical spectrum and by proposing a common lexicon as a point of reference for the clinical and research communities. The cornerstone of this lexicon is to consider AD solely as a clinical and symptomatic entity that encompasses both predementia and dementia phases.

Deposition of the amyloid-β peptide is a pathological hallmark of Alzheimer's disease. A high-throughput functional genomics screen identified G protein–coupled receptor 3 (GPR3), a constitutively active orphan G protein–coupled receptor, as a modulator of amyloid-β production. Overexpression of GPR3 stimulated amyloid-β production, whereas genetic ablation of GPR3 prevented accumulation of the amyloid-β peptide in vitro and in an Alzheimer's disease mouse model. GPR3 expression led to increased formation and cell-surface localization of the mature γ-secretase complex in the absence of an effect on Notch processing. GPR3 is highly expressed in areas of the normal human brain implicated in Alzheimer's disease and is elevated in the sporadic Alzheimer's disease brain. Thus, GPR3 represents a potential therapeutic target for the treatment of Alzheimer's disease.

Movement DisordersVolume 24, Issue 7 p. 1089-1090 Letter to the Editor Association of corticobasal degeneration and Huntington's disease: Can Tau aggregates protect Huntingtin toxicity? Dominique Caparros-Lefebvre MD, PhD, Corresponding Author Dominique Caparros-Lefebvre MD, PhD [email protected] Department of Neurology, Centre Hospitalier, Wattrelos, FranceDepartment of Neurology Centre Hospitalier Wattrelos, France===Search for more papers by this authorOlivier Kerdraon MD, Olivier Kerdraon MD Department of Neuropathology, CHRU, Lille, FranceSearch for more papers by this authorDavid Devos MD, PhD, David Devos MD, PhD Department of Neurology, CHRU, Lille, FranceSearch for more papers by this authorC.M. Dhaenens PharmD, PhD, C.M. Dhaenens PharmD, PhD Unit 837, JPARC, INSERM, Lille, FranceSearch for more papers by this authorDavid Blum PhD, David Blum PhD Unit 837, JPARC, INSERM, Lille, FranceSearch for more papers by this authorC.A Maurage MD, PhD, C.A Maurage MD, PhD Department of Neuropathology, CHRU, Lille, FranceSearch for more papers by this authorAndré Delacourte PhD, André Delacourte PhD Unit 837, JPARC, INSERM, Lille, FranceSearch for more papers by this authorBernard Sablonnière MD, PhD, Bernard Sablonnière MD, PhD Unit 837, JPARC, INSERM, Lille, FranceSearch for more papers by this author Dominique Caparros-Lefebvre MD, PhD, Corresponding Author Dominique Caparros-Lefebvre MD, PhD [email protected] Department of Neurology, Centre Hospitalier, Wattrelos, FranceDepartment of Neurology Centre Hospitalier Wattrelos, France===Search for more papers by this authorOlivier Kerdraon MD, Olivier Kerdraon MD Department of Neuropathology, CHRU, Lille, FranceSearch for more papers by this authorDavid Devos MD, PhD, David Devos MD, PhD Department of Neurology, CHRU, Lille, FranceSearch for more papers by this authorC.M. Dhaenens PharmD, PhD, C.M. Dhaenens PharmD, PhD Unit 837, JPARC, INSERM, Lille, FranceSearch for more papers by this authorDavid Blum PhD, David Blum PhD Unit 837, JPARC, INSERM, Lille, FranceSearch for more papers by this authorC.A Maurage MD, PhD, C.A Maurage MD, PhD Department of Neuropathology, CHRU, Lille, FranceSearch for more papers by this authorAndré Delacourte PhD, André Delacourte PhD Unit 837, JPARC, INSERM, Lille, FranceSearch for more papers by this authorBernard Sablonnière MD, PhD, Bernard Sablonnière MD, PhD Unit 837, JPARC, INSERM, Lille, FranceSearch for more papers by this author First published: 28 May 2009 https://doi.org/10.1002/mds.22204Citations: 18Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Josephs KA,Duffy JR,Strand EA, et al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 2006; 129: 1385–1398. 2 Feany MB,Dickson DW. Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am J Pathol 1995; 146: 1388–1396. 3 Buee-Scherrer V,Hof PR,Buee L, et al. Hyperphosphorylated tau proteins differentiate corticobasal degeneration and Pick's disease. Acta Neurpathol 1996; 91: 351–359. 4 Brinkman RR,Mezei MM,Theilmann J, et al. The likelihood of being affected with Huntington's disease by a particular age, for a specific CAG size. Am J Hum Genet 1997; 60: 1202–1210. 5 Vonsattel JP,Myers RH,Stevens TJ, et al. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 1985; 44: 559–577. 6 Li XJ,Friedman M. Interacting proteins as genetic modifiers of Huntington's disease. Trends Genet 2007; 23: 531–533. Citing Literature Volume24, Issue715 May 2009Pages 1089-1090 ReferencesRelatedInformation

The development of late onset Alzheimer disease (AD) is closely connected with cholesterol metabolism. Cholesterol increases the production and deposition of amyloid-β (Aβ) peptides, a hallmark of the pathology, and is abnormally retained in AD neurons. In the brain, cholesterol is synthesized in situ but cannot be degraded nor cross the blood-brain-barrier. The major exportable form of brain cholesterol is 24S-hydroxycholesterol, an oxysterol generated by the neuronal cholesterol 24-hydroxylase encoded by the CYP46A1 gene. To determine if CYP46A1 gene overexpression in the brain of APP23 mice affects the processing of APP and the production of amyloidogenic Aß peptides, we have injected stereotactically AAV vector expressing the human CYP46A1 gene in the cortex and hippocampus of 3-month old APP23 mice. Behavioral studies were performed at 6 months and mice were sacrified at 12 months to study the load of amyloid plaques, the production of Aß peptides, the levels of Aß oligomers and C-terminal fragments (CTFs), neuronal connectivity, microgliosis and astrocytosis. We demonstrate that increasing brain CYP46A1 gene expression through AAV-mediated gene transfer markedly reduces amyloid deposits, Aß40/42 peptides, Aß oligomers, reverses microgliosis and astrocytosis and improves spatial memory defects in APP23 mice before the onset of amyloid deposits. In vitro and in vivo studies converge to demonstrate that these effects are not mediated through the activation of ABCA1 and ApoE gene expression by 24S-hydroxycholesterol acting as ligand on liver-X receptors (LXR). Rather, in vitro and in vivo studies consistently suggest that the decrease of Aβ40/42 peptides induced by CYP46A1 gene expression is caused by a decreased γ-secretase cleavage of amyloid precursor protein. Overall, these data demonstrate that selective overexpression of CYP46A1 in neurons can reduce Aß peptides and amyloid deposits in vivo and indicate that viral vector delivery of CYP46A1 could find therapeutic applications in Alzheimer disease.

Clathrin-dependent endocytosis is mediated by a tightly regulated network of molecular interactions that provides essential protein-protein and protein-lipid binding activities. Here we report the hydrolysis of the alpha- and beta2-subunits of the tetrameric adaptor protein complex 2 by calpain. Calcium-dependent alpha- and beta2-adaptin hydrolysis was observed in several rat tissues, including brain and primary neuronal cultures. Neuronal alpha- and beta2-adaptin cleavage was inducible by glutamate stimulation and was accompanied by the decreased endocytosis of transferrin. Heterologous expression of truncated forms of the beta2-adaptin subunit significantly decreased the membrane recruitment of clathrin and inhibited clathrin-mediated receptor endocytosis. Moreover, the presence of truncated beta2-adaptin sensitized neurons to glutamate receptor-mediated excitotoxicity. Proteolysis of alpha- and beta2-adaptins, as well as the accessory clathrin adaptors epsin 1, adaptor protein 180, and the clathrin assembly lymphoid myeloid leukemia protein, was detected in brain tissues after experimentally induced ischemia and in cases of human Alzheimer disease. The present study further clarifies the central role of calpain in regulating clathrin-dependent endocytosis and provides evidence for a novel mechanism through which calpain activation may promote neurodegeneration: the sensitization of cells to glutamate-mediated excitotoxicity via the decreased internalization of surface receptors.

Several lines of evidence suggest that the glutamatergic system is severely impaired in Alzheimer disease (AD). Here, we assessed the status of glutamatergic terminals in AD using the first available specific markers, the vesicular glutamate transporters VGLUT1 and VGLUT2. We quantified VGLUT1 and VGLUT2 in the prefrontal dorsolateral cortex (Brodmann area 9) of controls and AD patients using specific antiserums. A dramatic decrease in VGLUT1 and VGLUT2 was observed in AD using Western blot. Similar decreases were observed in an independent group of subjects using immunoautoradiography. The VGLUT1 reduction was highly correlated with the degree of cognitive impairment, assessed with the clinical dementia rating (CDR) score. A significant albeit weaker correlation was also observed with VGLUT2. These findings provide evidence indicating that glutamatergic systems are severely impaired in the A9 region of AD patients and that this impairment is strongly correlated with the progression of cognitive decline. Our results suggest that VGLUT1 expression in the prefrontal cortex could be used as a valuable neurochemical marker of dementia in AD.

Neurofibrillary degeneration is often observed in the brain of patients with type I myotonic dystrophy (DM1). It consists principally of the aggregation of Tau isoforms that lack exon 2/3 encoded sequences, and is the consequence of the modified splicing of Tau pre-mRNA. In experimental models of DM1, the splicing of several transcripts is modified due to the loss of Muscleblind-like 1 (MBNL1) function. In the present study, we demonstrate that the MBNL1 protein is also present in the human brain, and consists of several isoforms, as shown by RT-PCR and sequencing. In comparison with controls, we show that the adult DM1 brain exhibits modifications in the splicing of MBNL1, with the preferential expression of long MBNL1 isoforms - a splicing pattern similar to that seen in the fetal human brain. In cultured HeLa cells, the presence of long CUG repeats, such as those found in the DM1 mutation, leads to similar changes in the splicing pattern of MBNL1, and the localization of MBNL1 in nuclear RNA foci. Long CUG repeats also reproduce the repression of Tau exon 2/3 inclusion, as in the human disease, suggesting that their effect on MBNL1 expression may lead to changes in Tau splicing. However, while an overall reduction in the expression of MBNL1 mimics the effect of the DM1 mutation, none of the MBNL1 isoforms tested so far modulates the endogenous splicing of Tau. The modified splicing of Tau thus results from a possibly CUG-mediated loss of function of MBNLI, but not from changes in the MBNLI expression pattern. (c) 2007 Elsevier Inc. All rights reserved.

Microtubule-associated Tau proteins belong to a family of factors that polymerize tubulin dimers and stabilize microtubules. Tau is strongly expressed in neurons, localized in the axon and is essential for neuronal plasticity and network. From the very beginning of Tau discovery, proteomics methods have been essential to the knowledge of Tau biochemistry and biology. In this review, we have summarized the main contributions of several proteomic methods in the understanding of Tau, including expression, post-translational modifications and structure, in both physiological and pathophysiological aspects. Finally, recent advances in proteomics technology are essential to develop further therapeutic targets and early predictive and discriminative diagnostic assays for Alzheimer’s disease and related disorders.

Gene dosage effects of Amyloid precursor protein (APP) can cause familial AD. Recent evidence suggest that microRNA (miRNA) pathways, implicated in gene transcriptional control, could be involved in the development of sporadic Alzheimer's disease (AD). We therefore investigated whether miRNAs could participate in the regulation of APP gene expression. We show that miRNAs belonging to the miR-20a family (that is, miR-20a, miR-17-5p and miR-106b) could regulate APP expression in vitro and at the endogenous level in neuronal cell lines. A tight correlation between these miRNAs and APP was found during brain development and in differentiating neurons. We thus identify miRNAs as novel endogenous regulators of APP expression, suggesting that variations in miRNA expression could contribute to changes in APP expression in the brain during development and disease. This possibility is further corroborated by the observation that a statistically significant decrease in miR-106b expression was found in sporadic AD patients.