Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers.

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage.

Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer's disease.

One of the earliest pathological features characterizing Alzheimer's disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling.

Molecular subtypes of Alzheimer's disease.

Protein misfolding and aggregation is a central feature of several neurodegenerative disorders including Alzheimer's disease (AD), in which assemblies of amyloid β (Aβ) peptides accumulate in the brain in the form of parenchymal and/or vascular amyloid. A widely accepted concept is that AD is characterized by distinct clinical and neuropathological phenotypes. Recent studies revealed that Aβ assemblies might have structural differences among AD brains and that such pleomorphic assemblies can correlate with distinct disease phenotypes.

Altered Expression of Circulating Cdc42 in Frontotemporal Lobar Degeneration.

The term frontotemporal lobar degeneration (FTLD) defines a group of heterogeneous conditions histologically characterized by neuronal degeneration, inclusions of various proteins, and synaptic loss. However, the molecular mechanisms contributing to these alterations are still unknown. As the Rho-GTPase family member Cell division cycle 42 (Cdc42) plays a key role in the regulation of actin cytoskeleton dynamics and spine formation, we investigated whether Cdc42 protein levels were altered in the disease.

Tau Rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study.

Background: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies.

Loss of exosomes in progranulin-associated frontotemporal dementia.

Many cells of the nervous system have been shown to release exosomes, a subclass of secreted vesicles of endosomal origin capable of transferring biomolecules among cells: this transfer modality represents a novel physiological form of intercellular communication between neural cells. Herein, we demonstrated that progranulin (PGRN), a protein targeted to the classical secretory pathway, is also secreted in association with exosomes by human primary fibroblasts. Moreover, we demonstrated that null mutations in the progranulin gene (GRN), a major cause of frontotemporal dementia, strongly reduce the number of released exosomes and alter their composition.

Value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease.

Objective: Meta-analyses show that nonbound ceruloplasmin (non-Cp) copper (also known as free or labile copper) in serum is higher in patients with Alzheimer disease (AD). It differentiates subjects with mild cognitive impairment (MCI) from healthy controls. However, a longitudinal study on an MCI cohort has not yet been performed to assess the accuracy of non-Cp copper for the prediction of conversion from MCI to AD during a long-term follow-up.

Expression of A2V-mutated Aβ in Caenorhabditis elegans results in oligomer formation and toxicity.

Although Alzheimer's disease (AD) is usually sporadic, in a small proportion of cases it is familial and can be linked to mutations in β-amyloid precursor protein (APP). Unlike the other genetic defects, the mutation [alanine-673→valine-673] (A673V) causes the disease only in the homozygous condition with enhanced amyloid β (Aβ) production and aggregation; heterozygous carriers remain unaffected. It is not clear how misfolding and aggregation of Aβ is affected in vivo by this mutation and whether this correlates with its toxic effects.

C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: a genotype-phenotype correlation study.

Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide repeat pathological expansion in a large cohort of familial and sporadic FTLD and related disorders (FTLD and related disorders, n = 388; Controls, n = 201). Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking into account the hexanucleotide repeat units number as a possible disease modifier.

Secretory leukocyte protease inhibitor protein regulates the penetrance of frontotemporal lobar degeneration in progranulin mutation carriers.

The discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases leading to dementia has brought renewed interest in progranulin and its functions in the central nervous system. Full length progranulin is preserved from cleavage by secretory leukocyte protease inhibitor (SLPI), one of the smallest serine protease inhibitor circulating in plasma. Herein, we investigated the relationship between circulating SLPI and progranulin in affected and unaffected subjects belonging to 26 Italian pedigrees carrying GRN null mutations.

Circulating progranulin as a biomarker for neurodegenerative diseases.

Progranulin is a growth factor involved in the regulation of multiple processes including tumorigenesis, wound repair, development, and inflammation. The recent discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD), and other neurodegenerative diseases leading to dementia, has brought renewed interest in progranulin and its functions in the central nervous system. GRN null mutations cause protein haploinsufficiency, leading to a significant decrease in progranulin levels that can be detected in plasma, serum and cerebrospinal fluid (CSF) of mutation carriers.

Distinct cerebrospinal fluid amyloid-beta peptide signatures in cognitive decline associated with Alzheimer's disease and schizophrenia.

Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). Cognitive deficits are prevalent in patients with schizophrenia (SCZ) and worsen with old age. We recently reported that elderly SCZ patients show reduced levels of amyloid-beta (Aβ)1-42 in cerebrospinal fluid (CSF).

Translational proteomics in Alzheimer's disease and related disorders.

Alzheimer's disease (AD) and its related syndromes--especially frontotemporal dementia (FTD), Lewy body dementia (LBD) and dementias associated with cerebrovascular disease--are the principal causes of dementia. Until a recent period, the diagnosis of AD and its related disorders relied almost exclusively on the combination of a neurological examination and the use neuropsychological tests. Cerebrospinal fluid (CSF) dosage of neuropathologically AD-associated proteins has already been incorporated into the neurochemical diagnosis of AD, attesting the relevance of translational research.

Estimating the age of the most common Italian GRN mutation: walking back to Canossa times.

Mutations in the progranulin gene (GRN) were first implicated in frontotemporal lobar degeneration in 2006. The GRN p.Leu271LeufsX10 mutation is one of the most common GRN mutations worldwide.

Losing protein in the brain: the case of progranulin.

It is well known that progranulin protein is involved in wound repair, inflammation, and tumor formation. The wedding between progranulin and brain was celebrated in 2006 with the involvement of progranulin gene (GRN) in Frontotemporal lobar degeneration (FTLD), the most common form of early-onset dementia: up to date, 75 mutations have been detected in FTLD patients as well as in patients with widely variable clinical phenotypes. All pathogenic GRN mutations identified thus far cause the disease through a uniform mechanism, i.

Optimal plasma progranulin cutoff value for predicting null progranulin mutations in neurodegenerative diseases: a multicenter Italian study.

Background: Recently, attention was drawn to a role for progranulin in the central nervous system with the identification of mutations in the progranulin gene (GRN) as an important cause of frontotemporal lobar degeneration. GRN mutations are associated with a strong reduction of circulating progranulin and widely variable clinical phenotypes: thus, the dosage of plasma progranulin is a useful tool for a quick and inexpensive large-scale screening of carriers of GRN mutations.

Objective: To establish the best cutoff threshold for normal versus abnormal levels of plasma progranulin.

A window into the heterogeneity of human cerebrospinal fluid Aβ peptides.

The initiating event in Alzheimer's disease (AD) is an imbalance in the production and clearance of amyloid beta (Aβ) peptides leading to the formation of neurotoxic brain Aβ assemblies. Cerebrospinal Fluid (CSF), which is a continuum of the brain, is an obvious source of markers reflecting central neuropathologic features of brain diseases. In this review, we provide an overview and update on our current understanding of the pathobiology of human CSF Aβ peptides.

Cerebrospinal fluid biomarkers for Alzheimer's disease: the present and the future.

Alzheimer's disease (AD) is the major cause of dementia in the elderly. The biochemical changes that precede AD may be present up to 20 years before the clinical manifestation of the disease. The translational development of AD biomarkers may be theoretically achieved via two different strategies: the first strategy can be defined as 'knowledge-based' (deductive method), while the second one is a hypothesis-generating 'unbiased' approach (inductive strategy).

Optimization protocol for amyloid-β peptides detection in human cerebrospinal fluid using SELDI TOF MS.

Purpose: The aim of the present work was to set up an optimized protocol for human cerebrospinal fluid amyloid-β (Aβ) profiling.

Experimental Design: We devised an immunoproteomic assay that employs monoclonal antibodies (mAbs) on Preactivated Surface (PS20) chip array followed by SELDI TOF MS. A comparison of a number of factors was performed, and the impact of these differences was noted.

Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer's disease.

It has recently become clear that proteins associated with neurodegenerative disorders can be selectively incorporated into intraluminal vesicles of multivesicular bodies and subsequently released within exosomes. Multiple lines of research support a neuroprotective role for cystatin C in Alzheimer's disease (AD). Herein we demonstrate that cystatin C, a protein targeted to the classical secretory pathway by its signal peptide sequence, is also secreted by mouse primary neurons in association with exosomes.

Novel T719P AbetaPP mutation unbalances the relative proportion of amyloid-beta peptides.

A novel missense mutation (T719P) in the amyloid-beta protein precursor (AbetaPP) gene was discovered in a 46-year old patient affected by early onset familial Alzheimer's disease. Using surface enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS), we determined mass profiles of amyloid-beta peptides (Abeta) in cerebrospinal fluid (CSF) of the AbetaPP mutated patient, healthy control subjects (n = 10), and of two subjects carrying mutations in presenilins genes (PS) (i.e.

Presenilin 2 is secreted in mouse primary neurons: a release enhanced by apoptosis.

Presenilin 1 (PS1) and presenilin 2 (PS2) are homologous transmembrane proteins genetically associated with Alzheimer disease. As previously reported by our group for PS1, here we demonstrated that, in mouse primary neurons and microglial cells, PS2 C-terminal fragment (CTF) is released by shedding into the extracellular compartment as a soluble form and that this release is 4.07-fold increased during apoptosis.