Luca Giliberto

• FIMR

Plasma levels of protein biomarkers glial fibrillary acidic protein (GFAP) and neurofilament light (NEFL) are key dementia biomarkers, but it is unclear how risk genes for Alzheimer s disease (AD) influence levels of these biomarkers. We investigated the association of the established high-effect variants for AD in APOE and TREM2 with these biomark...

Tau is a primary target for immunotherapy in Alzheimer’s disease. Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo . Here, we compared the effects of single-chain variable fragments (scFv) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used a...

Fluorodeoxyglucose F18 (FDG) positron emission tomography (PET) imaging can help clinicians pursue the differential diagnosis of various neurodegenerative diseases. It has become an invaluable diagnostic tool in routine clinical practice in conjunction with computed tomography (CT) imaging, magnetic resonance imaging (MRI), and biomarker studies. W...

APOE is a major genetic factor in late-onset Alzheimer’s disease (LOAD), with APOE4 increasing risk, APOE3 acting as neutral, and APOE2 offering protection. APOE also plays key role in lipid metabolism, affecting both peripheral and central systems, particularly in lipoprotein metabolism in triglyceride and cholesterol regulation. APOE2 is linked t...

Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy caused by misfolded human prion proteins (PrP)s. Due to variability in presentation, the diagnosis may be missed in lieu of various psychiatric disorders. Our study reports on a prototypical case and psychiatric mimic for CJD, and the workup used to establish the correct diagnosis. A 54...

We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer’s disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and...

The transcription factor NRF2 plays a crucial role in the regulation of antioxidant cell responses to stressors. It controls a plethora of genes with pro-surviving activity, among which heme oxygenase 1 (HO-1) has been recognized to play a potent anti-inflammatory activity through its metabolites carbon monoxide (CO) and bilirubin. Macrophages trig...

About 2% of Alzheimer's disease (AD) cases have early onset (FAD) and are caused by mutations in either Presenilins (PSEN1/2) or Amyloid-β Precursor Protein (APP). PSEN1/2 catalyze production of Aβ peptides of different length from APP. Aβ peptides are the major components of amyloid plaques, a pathological lesion that characterizes AD. Analysis of...

Alzheimer’s disease (AD) is the most common form of dementia, affecting in excess of 5 million Americans and 50 million people worldwide. The cost, personal and financial, to manage AD is superior to any single chronic disease of the ageing population, and its burden is only increasing with time. In order to properly manage these patients, we need...

Alzheimer’s disease (AD) is the most common type of dementia, affecting more than 5 million Americans, with steadily increasing mortality and incredible socio-economic burden. Not only have therapeutic efforts so far failed to reach significant efficacy, but the real pathogenesis of the disease is still obscure. The current theories are based on pa...

Abstract With evidence supporting the prion-like spreading of extracellular tau as a mechanism for the initiation and progression of Alzheimer’s disease (AD), immunotherapy has emerged as a potential disease-modifying strategy to target tau. Many studies have proven effective to clear pathological tau species in animal models of AD, and several cli...

Tau, the main component of the neurofibrillary tangles (NFTs), is an attractive target for immunotherapy in Alzheimer’s disease (AD) and other tauopathies. MC1/Alz50 are currently the only antibodies targeting a disease-specific conformational modification of tau. Passive immunization experiments using intra-peritoneal injections have previously sh...

Symptoms of psychosis in patients with Alzheimer disease may be the expression of a pathological subtype associated with an accelerated cognitive and functional deterioration portending a hastened mortality.¹ The proposed National Institute of Mental Health Research Domain Criteria initiative provides a framework for conceptualizing the common neur...

TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by...

Amyloid-β 1-42 accumulation is the major pathogenetic event in Alzheimer's disease (AD), believed to be responsible for synaptic dysfunction and neuronal cell death. However, the physiologic activity of Aβ peptides remains elusive: Aβ might not only play a toxic role, but also act as a functional signaling intermediate. We recently reported that Aβ...

The sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the amyloid-β protein precursor (AβPP) result in the production of the amyloid-β (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of small, soluble aggregates of Aβ42 is the major pathogenic eve...

An autosomal dominant mutation in the BRI2/ITM2B gene causes familial Danish dementia (FDD). Analysis of FDD(KI) mice, a mouse model of FDD genetically congruous to the human disease since they carry one mutant and one wild-type Bri2/Itm2b allele, has shown that the Danish mutation causes loss of Bri2 protein, synaptic plasticity and memory impairm...

The pathogenesis of Alzheimer's disease is attributed to misfolding of Amyloid-β (Aβ) peptides. Aβ is generated during amyloidogenic processing of Aβ-precursor protein (APP). Another characteristic of the AD brain is increased phosphorylation of APP amino acid Tyr(682). Tyr(682) is part of the Y(682)ENPTY(687) motif, a docking site for interaction...

Familial dementias, which include Alzheimer disease (AD), familial British dementia (FBD), and familial Danish dementia (FDD), are caused by dominantly inherited autosomal mutations and are characterized by the production of amyloidogenic peptides, neurofibrillary tangles (NFTs) and neurodegeneration (St George-Hyslop and Petit, 2005; Garringer et...

Regulated intramembranous proteolysis of the amyloid-beta precursor protein by the gamma-secretase yields amyloid-beta, which is the major component of the amyloid plaques found in Alzheimer's disease (AD), and the APP intracellular domain (AID). In vitro studies have involved AID in apoptosis and gene transcription. In vivo studies, which utilize...

To develop a blood-based test for screening populations at risk for Alzheimer disease. Case-control study. Subjects A total of 180 patients with mild cognitive impairment (MCI) and 105 age-matched, cognitively normal controls. The titer of beta-amyloid 1-42 autoantibodies in the plasma was obtained at the time of diagnosis and evaluated by enzyme-l...

Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-beta (Abeta) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Abeta level...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting the elderly population. Mechanistically, the major cause of the disease bases on the altered processing of the amyloid-beta (Abeta) precursor protein (APP), resulting in the accumulation and aggregation of neurotoxic forms of Abeta. Abeta derives from the sequential prot...

Mutations in the integral membrane protein 2B, also known as BRI(2), a type II trans-membrane domain protein cause two autosomal dominant neurodegenerative diseases, Familial British and Danish Dementia. In these conditions, accumulation of a C-terminal peptide (ABri and ADan) cleaved off from the mutated precursor protein by the pro-protein conver...

The effects of amyloid-beta are extremely complex. Current work in the field of Alzheimer disease is focusing on discerning the impact between the physiological signaling effects of soluble low molecular weight amyloid-beta species and the more global cellular damage that could derive from highly concentrated and/or aggregated amyloid. Being able t...

Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimer's disease (AD). We measured plasma levels of amyloid-β40 (Aβ40) and Aβ42 in 191 subjects with aMCI. Seventy-nine of them were clinically followed for two years. In the total cohort of aMCI cases, the average level of Aβ42, as well as the Aβ42/Aβ40 ratio, was sign...

While it is well established that stroke and cerebral hypoperfusion are both significant risk factors for Alzheimer's disease, the molecular link between ischemia and amyloid precursor protein processing has only been recently established. Specifically, hypoxia significantly increases beta-site APP cleaving enzyme (BACE1) gene transcription through...

Mutations of the presenilin 1 (PS1) gene are the most common cause of early onset familial Alzheimer disease (FAD). PS1 mutations alter the activity of the γ-secretase on the β-amyloid precursor protein (APP), leading to selective overproduction of β-amyloid (Aβ) 42 peptides, the species that forms oligomers that may exert toxic effects on neurons....

Regulated intramembrane proteolysis of the beta-amyloid precursor protein by the gamma-secretase yields two peptides. One, amyloid-beta, is the major component of the amyloid plaques found in Alzheimer's disease patients. The other, APP IntraCellular Domain, has been involved in regulation of apoptosis, calcium flux and gene transcription. To date,...

Genetic alterations of amyloid beta-peptide (Abeta) production caused by mutations in the Abeta precursor protein (APP) cause familial Alzheimer's disease (AD). Mutations in BRI2, a gene of undefined function, are linked to familial British and Danish dementias, which are pathologically and clinically similar to Alzheimer's disease. We report that...

The activity of beta-secretase (BACE1), the endo-protease essential for the production of amyloid beta (Abeta) peptides, is increased in brain of late-onset sporadic Alzheimer's disease (AD), and oxidative stress is the potential cause of this event. Oxidative stress up-regulates the expression and the activity of BACE1 in cellular and animal model...

Sequential cleavages of the beta-amyloid precursor protein cleaving enzyme 1 (BACE1) by beta-secretase and gamma-secretase generate the amyloid beta-peptides, believed to be responsible of synaptic dysfunction and neuronal cell death in Alzheimer's disease (AD). Levels of BACE1 are increased in vulnerable regions of the AD brain, but the underlying...

Epidemiological and experimental data suggest that type 2 diabetes (DM2) and sporadic late-onset Alzheimer's disease (AD) share a common mechanism, that is able to produce accumulation of insulin and amyloid β42 (Aβ42), the major pathogenic events respectively of the two conditions. In 71 non diabetic patients with amnestic mild cognitive impairmen...

The mechanism of neurodegeneration caused by β-amyloid in Alzheimer disease is controversial. Neuronal toxicity is exerted mostly by various species of soluble β-amyloid oligomers that differ in their N- and C-terminal domains. However, abundant accumulation of β-amyloid also occurs in the brains of cognitively normal elderly people, in the absence...

Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid-β (Aβ) peptides, which are derive from processing of the β-amyloid precursor protein (APP), better named amyloid-β precursor protein (AβPP),...

Accumulation in the brain of small aggregates of amyloid beta-protein 42 (Abeta42) is the major pathogenic event of Alzheimer disease (AD). In familial early-onset AD this event is likely the result of Abeta42 overproduction; in the most common sporadic late-onset form of the disease the mechanisms of Abeta42 accumulation are unknown. To address th...

Scavenger receptors recently have been related to Alzheimer's disease, although it is still unclear whether they contribute to the pathogenesis of the disease or reflect an inflammatory response to the deposition of amyloid beta-protein (Abeta). In this study we demonstrate that CD36, a class B scavenger receptor, is highly expressed in the cerebra...

Progressive supranuclear palsy (PSP) is characterized by a pure neurofibrillary tau pathology involving mainly basal ganglia and brainstem nuclei. In addition to a haplotype of the tau gene potentially favoring tau aggregation, lipoperoxidation has been shown to be associated with PSP tau pathology. To analyze cdk5/p35 complex, a kinase that regula...