Luciano D'Adamio

• Doctor of Medicine
• Professor (Full) at Rutgers New Jersey Medical School

Delivery of therapeutics to the brain is restricted by the blood-brain barrier (BBB). A promising strategy to overcome this involves exploiting receptor-mediated transcytosis pathways, such as those mediated by transferrin receptor 1 (TfR1), which is highly expressed on brain endothelial cells and naturally transports iron-bound transferrin across...

Familial Danish Dementia (FDD) is a rare autosomal dominant neurodegenerative disorder caused by a mutation in the integral membrane protein 2B ( ITM2b ) gene. Clinically, FDD is characterized by cerebral amyloid angiopathy (CAA), cerebellar ataxia, and dementia. Notably, FDD shares several neuropathological features with Alzheimer’s disease (AD),...

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...

APOE is a major genetic factor in late-onset Alzheimer's disease (LOAD), with APOE4 significantly increasing risk, APOE3 acting as a neutral isoform, and APOE2 offering protective effects. The primary hypothesis links APOE isoforms to LOAD through their impact on Aβ production and deposition, which is thought to be related to their effects on lipid...

ITM2B/BRI2 mutations cause Alzheimer’s Disease (AD)-related dementias. We observe heightened ITM2B/BRI2 expression in microglia, a pivotal cell type in AD due to risk-increasing variants in the microglial gene TREM2 . Single-cell RNA-sequencing demonstrates a Trem2/Bri2-dependent microglia cluster, underscoring their functional interaction. α-secre...

Background Several studies including ours reported the detrimental effects of extracellular tau oligomers (ex‐oTau) on glutamatergic synaptic transmission and plasticity. Astrocytes greatly internalize ex‐oTau thus contributing to their clearance. However, glial cell engulfment of oTau leads to alteration of neuro/gliotransmitter handling that nega...

Background Amyloid precursor protein (APP) is a transmembrane protein expressed at the synapse throughout life. In absence of APP, extracellular Aß‐ and tau‐oligomers no longer impair memory and its synaptic surrogate, long‐term potentiation (LTP). Synapses include pre‐ and post‐synaptic compartments. However, the relative role of pre‐ vs. post‐syn...

Model organisms of human diseases are invaluable tools for unraveling pathogenic mechanisms, identifying potential targets for drug development, and evaluating the therapeutic efficacy of candidates in preclinical trials. The utility of model organisms hinges upon their ability to faithfully replicate the underlying pathogenic mechanisms of the hum...

ITM2B/BRI2 mutations cause familial forms of Alzheimer disease (AD)-related dementias by disrupting BRI2 protein function and leading to the accumulation of amyloidogenic peptides. Although typically studied in neurons, our findings show that BRI2 is highly expressed in microglia, which are crucial in AD pathogenesis due to the association of varia...

Several studies including ours reported the detrimental effects of extracellular tau oligomers (ex-oTau) on glutamatergic synaptic transmission and plasticity. Astrocytes greatly internalize ex-oTau whose intracellular accumulation alters neuro/gliotransmitter handling thereby negatively affecting synaptic function. Both amyloid precursor protein (...

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...

Background While most Alzheimer’s disease cases are sporadic with late onset (LOAD), ~ 2% of cases are inherited, have an early onset, and are caused by mutations in Presenilins (PSEN1/2) or Amyloid-β Precursor Protein (APP) genes (familial AD, FAD). PSEN1/2 are the catalytic component of γ-secretase, a protease that generates Aβ peptides of differ...

Cleavage of Amyloid precursor protein by β- and γ-secretases lead to Aβ formation. The widely accepted pathogenic model states that these mutations cause AD via an increase in Aβ formation and accumulation of Aβ in Amyloid plaques. APP mutations cause early onset familial forms of Alzheimer’s disease (FAD) in humans. We generated App−Swedish (Apps)...

Model organisms mimicking the pathogenesis of human diseases are useful for identifying pathogenic mechanisms and testing therapeutic efficacy of compounds targeting them. Models of Alzheimer’s disease (AD) and related dementias (ADRD) aim to reproduce the brain pathology associated with these neurodegenerative disorders. Transgenic models, which i...

Model organisms mimicking the pathogenesis of human diseases are useful for identifying pathogenic mechanisms and testing therapeutic efficacy of compounds targeting them. Models of Alzheimer’s disease and related dementias aim to reproduce the brain pathology associated with these neurodegenerative disorders. Transgenic models, which involve rando...

Familial British and Danish dementia (FBD and FDD) are neurodegenerative disorders caused by mutations in the gene integral membrane protein 2B (ITM2b) encoding BRI2, which tunes excitatory synaptic transmission at both pre- and post-synaptic termini. In addition, BRI2 interacts with and modulates proteolytic processing of Amyloid-β precursor Prote...

Familial British and Danish dementia (FBD and FDD) are two neurodegenerative disorders caused by mutations in the Integral membrane protein 2B (ITM2b). BRI2, the protein encoded by ITM2b, tunes excitatory synaptic transmission at both pre- and post-synaptic terminus. Too, BRI2 interacts with and modulates proteolytic processing of Amyloid-β precurs...

Alzheimer’s disease is a neurodegenerative dementia associated with deposition in the central nervous system (CNS) of amyloid plaques and neurofibrillary tangles, formed by Aβ peptides and phosphor-tau, respectively. ~2% of AD cases are due to familial mutations (FAD); ~98% of cases are sporadic (SAD). FAD animal models are commonly used to study S...

The Amyloid Precursor Protein (APP) undergoes extensive proteolytic processing to produce several biologically active metabolites which affect Alzheimer’s disease (AD) pathogenesis. Sequential cleavage of APP by β- and γ-secretases results in Aβ, while cleavage by α- and γ-secretases produces the smaller p3 peptide. Here we report that in cells in...

Mutations in Integral membrane protein 2B (ITM2b/BRI2) gene causes familial British and Danish dementia (FBD and FDD), autosomal dominant disorders characterized by progressive cognitive deterioration. Two pathogenic mechanisms, which may not be mutually exclusive, have been proposed for FDD and FBD: 1) loss of BRI2 function; 2) accumulation of amy...

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...

Trem2R47H rats, which carry the Alzheimer disease (AD) risk factor p.R47H variant of the microglia gene TREM2 and produce human Abeta. Previously, we demonstrated that supraphysiological TNF-alpha; boost glutamatergic transmission and suppresses Long-term-Potentiation (LTP), a surrogate of learning and memory, in peri-adolescent Trem2R47H rats (Ren...

15 To study the mechanisms by which the p.R47H variant of the microglia gene and Alzheimer's 16 disease (AD) risk factor TREM2 increases dementia risk, we created Trem2 R47H KI rats. 17 Trem2 R47H rats were engineered to produce human Aβ to define human-Aβ-dependent and-18 independent pathogenic mechanisms triggered by this variant. Interestingly,...

To study the mechanisms by which the p.R47H variant of the microglia gene and Alzheimer's disease (AD) risk factor TREM2 increases dementia risk, we created Trem2R47H KI rats. Trem2R47H rats were engineered to produce human Aβ to define human-Aβ-dependent and -independent pathogenic mechanisms triggered by this variant. Interestingly, pre- and peri...

To study the mechanisms by which the p.R47H variant of the microglia gene and Alzheimer’s disease (AD) risk factor TREM2 increases dementia risk, we created Trem2R47H KI rats. Trem2R47H rats were engineered to produce human Aβ to define human-Aβ-dependent and -independent pathogenic mechanisms triggered by this variant. Interestingly, pre- and peri...

To study the mechanisms by which the p.R47H variant of the microglia gene and Alzheimer’s disease (AD) risk factor TREM2 increases dementia risk, we created Trem2R47H KI rats. Trem2R47H rats were engineered to produce human Aβ to define human-Aβ-dependent and -independent pathogenic mechanisms triggered by this variant. Interestingly, pre- and peri...

The amyloid hypothesis posits that the amyloid-beta (Aβ) protein precedes and requires microtubule-associated protein tau in a sort of trigger-bullet mechanism leading to Alzheimer's disease (AD) pathology. This sequence of events has become dogmatic in the AD field and is used to explain clinical trial failures due to a late start of the intervent...

Familial forms of Alzheimer’s disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein (APP), whose processing can result in the formation of amyloid β (Aβ). FAD can also result from mutations in the presenilin 1/2 (PSEN1/2 ) genes, whose protein products partially compose the γ-secretase complex that cleaves Aβ from APP...

The R47H variant of the Triggering-Receptor-Expressed on Myeloid cells 2 (TREM2) increases the risk of Alzheimer’s disease (AD). Mutagenesis of exon 2 in Knock-in (KI) mouse models of the R47H variant introduced a cryptic splice site, leading to nonsense mediated decay. Since haploinsufficiency does not model Trem2-R47H function, a new rat KI model...

Cleavage of APP by BACE1/b-secretase initiates the amyloidogenic cascade leading to Amyloid-b (Ab) production. a-Secretase initiates the non-amyloidogenic pathway preventing Ab production. Several APP mutations cause familial Alzheimer's disease (AD), while the Icelandic APP mutation near the BACE1-cleavage site protects from sporadic dementia, emp...

Background: Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer's disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown. Methods: This work used a combination of biochemic...

Amyloid precursor protein (APP) modulates glutamate release via cytoplasmic and intravesicular interactions with the synaptic vesicle release machinery. The intravesicular domain, called ISVAID, contains the BACE1 cleavage site of APP. We have tested the functional significance of BACE1 processing of APP using App‐Swedish (Apps) knock‐in rats, whic...

Amyloid precursor protein (APP), whose mutations cause familial Alzheimer's disease (FAD), modulates neurotransmission via interaction of its cytoplasmic tail with the synaptic release machinery. Here we identified an intra-vesicular domain of APP, called ISVAID, that interacts with glutamatergic but not GABAergic synaptic vesicle proteins. ISVAID...

Mutations in the Integral membrane protein 2B (ITM2b/BRI2) gene, which codes for a protein called BRI2, cause familial British and Danish dementia (FBD and FDD). Loss of BRI2 function and/or accumulation of amyloidogenic mutant BRI2-derived peptides have been proposed to mediate FDD and FBD pathogenesis by impairing synaptic Long-term potentiation...

The “Amyloid Cascade Hypothesis” has dominated the Alzheimer’s disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-bas...

A homozygous nonsense mutation in the cereblon (CRBN) gene results in autosomal recessive, nonsyndromic intellectual disability that is devoid of other phenotypic features, suggesting a critical role of CRBN in mediating learning and memory. In this study, we demonstrate that adult male Crbn knock-out (CrbnKO) mice exhibit deficits in hippocampal-d...

Tau plays a pivotal role in the pathogenesis of neurodegenerative disorders: mutations in the gene encoding for tau (MAPT) are linked to Fronto-temporal Dementia (FTD) and hyper-phosphorylated aggregates of tau forming neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. Accordingly, tau is a fav...

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...

Data relating to Figure 2E–F.DOI: http://dx.doi.org/10.7554/eLife.26991.005

Data relating to Figure 2B–C.DOI: http://dx.doi.org/10.7554/eLife.26991.004

Data relating to Figure 2G–H.DOI: http://dx.doi.org/10.7554/eLife.26991.006

Data relating to Figure 3G–H.DOI: http://dx.doi.org/10.7554/eLife.26991.011

Data relating to Figure 4A–B–C.DOI: http://dx.doi.org/10.7554/eLife.26991.013

Data relating to Figure 5D.DOI: http://dx.doi.org/10.7554/eLife.26991.020

Data relating to Figure 4D–E–F.DOI: http://dx.doi.org/10.7554/eLife.26991.014

Data relating to Figure 2I–J.DOI: http://dx.doi.org/10.7554/eLife.26991.007

Data relating to Figure 3A–B–C.DOI: http://dx.doi.org/10.7554/eLife.26991.009

Data relating to Figure 3D–E–F.DOI: http://dx.doi.org/10.7554/eLife.26991.010

Data relating to Figure 4G–H.DOI: http://dx.doi.org/10.7554/eLife.26991.015

Data relating to Figure 5B.DOI: http://dx.doi.org/10.7554/eLife.26991.018

Data relating to Figure 5C.DOI: http://dx.doi.org/10.7554/eLife.26991.019

Data relating to Figure 5A.DOI: http://dx.doi.org/10.7554/eLife.26991.017

Data relating to Figure 5F.DOI: http://dx.doi.org/10.7554/eLife.26991.022

Data relating to Figure 5G.DOI: http://dx.doi.org/10.7554/eLife.26991.023

Data relating to Figure 5E.DOI: http://dx.doi.org/10.7554/eLife.26991.021

The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAβ and oTau share a co...

The Amyloid precursor protein (APP), whose mutations cause Alzheimer's disease, plays an important in vivo role and facilitates transmitter release. Since the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the Ubiquitin-Proteasome-...

Mutations in BRI2/ITM2b genes cause Familial British and Danish Dementias (FBD and FDD), which are pathogenically similar to Familial Alzheimer Disease (FAD). BRI2 inhibits processing of Amyloid precursor protein (APP), a protein involved in FAD pathogenesis. Accumulation of a carboxyl-terminal APP metabolite -ß-CTF- causes memory deficits in a kno...

Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer’s disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leadin...

Source data for statistical analysis of frequency facilitation at 5 Hz in Figure 3C.DOI: http://dx.doi.org/10.7554/eLife.09743.010

Source data for statistical analysis of frequency facilitation at 20 Hz in Figure 3C.DOI: http://dx.doi.org/10.7554/eLife.09743.012

Source data for statistical analysis of decay rate shown in Figure 5A.DOI: http://dx.doi.org/10.7554/eLife.09743.016

Source data for statistical analysis of decay rate shown in Figure 5B.DOI: http://dx.doi.org/10.7554/eLife.09743.017

Source data for statistical analysis of input/output curves in Figure 7A.DOI: http://dx.doi.org/10.7554/eLife.09743.020

Source data for statistical analysis of paired-pulse facilitation in Figure 7B.DOI: http://dx.doi.org/10.7554/eLife.09743.021

Source data for statistical analysis of paired-pulse facilitation in Figure 9B.DOI: http://dx.doi.org/10.7554/eLife.09743.027

Source data for statistical analysis of input/output curves in Figure 11A.DOI: http://dx.doi.org/10.7554/eLife.09743.032

Source data for statistical analysis of mEPSCs frequency in Figure 12A.DOI: http://dx.doi.org/10.7554/eLife.09743.036

Source data for statistical analysis of mEPSCs decay time in Figure 12B.DOI: http://dx.doi.org/10.7554/eLife.09743.037

Source data for statistical analysis of frequency facilitation at 1 Hz in Figure 3C.DOI: http://dx.doi.org/10.7554/eLife.09743.009

Source data for statistical analysis of mEPSCs frequency in Figure 8A.DOI: http://dx.doi.org/10.7554/eLife.09743.024

Source data for statistical analysis of input/output curves in Figure 9A.DOI: http://dx.doi.org/10.7554/eLife.09743.026

Source data for statistical analysis of frequency facilitation at 20 Hz in Figure 9C.DOI: http://dx.doi.org/10.7554/eLife.09743.028

Source data for statistical analysis of input/output curves in Figure 3A.DOI: http://dx.doi.org/10.7554/eLife.09743.007

Source data for statistical analysis of mEPSCs frequency in Figure 4A.DOI: http://dx.doi.org/10.7554/eLife.09743.014

Source data for statistical analysis of paired-pulse facilitation in Figure 11B.DOI: http://dx.doi.org/10.7554/eLife.09743.033

Source data for statistical analysis of paired-pulse facilitation in Figure 3B.DOI: http://dx.doi.org/10.7554/eLife.09743.008

Source data for statistical analysis of frequency facilitation at 10 Hz in Figure 3C.DOI: http://dx.doi.org/10.7554/eLife.09743.011

Source data for statistical analysis of frequency facilitation at 20 Hz in Figure 7C.DOI: http://dx.doi.org/10.7554/eLife.09743.022

Source data for statistical analysis of frequency facilitation at 20Hz in Figure 11C.DOI: http://dx.doi.org/10.7554/eLife.09743.034

The amyloid precursor protein (APP), whose mutations cause familial Alzheimer's disease, interacts with the synaptic release machinery, suggesting a role in neurotransmission. Here we mapped this interaction to the NH 2-terminal region of the APP intracellular domain. A peptide encompassing this binding domain-named JCasp-is naturally produced by a...

Amyloid Precursor Protein (APP) is a type I membrane protein that undergoes extensive processing by secretases, including BACE1. Although mutations in APP and genes that regulate processing of APP, such as PSENs and BRI2/ITM2B, cause dementias, the normal function of APP in synaptic transmission, synaptic plasticity and memory formation is poorly u...

The Presenilins (PS) gene family is composed of two members: PS1 and PS2. Mutations in PSs are linked to familial Alzheimer's disease (FAD) (1). PSs are the catalytic subunits of the γ-secretase multimolecular complex, which mediates the intramembranous cleavage of many type I membrane proteins, including amyloid precursor protein (APP) and Notch (...

Mutations in ß and genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, called FDD, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPß/...

Background Mutations in either Aβ Precursor protein (APP) or genes that regulate APP processing, such as BRI2/ITM2B and PSEN1/PSEN2, cause familial dementias. Although dementias due to APP/PSEN1/PSEN2 mutations are classified as familial Alzheimer disease (FAD) and those due to mutations in BRI2/ITM2B as British and Danish dementias (FBD, FDD), dat...

Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the (682) YENPTY(687) motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y(682)...

A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid-β precursor protein (APP) processing, which is genetically linked to Alzheimer's disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by β...

A dominant mutation in the ITM2B/BRI2 gene causes familial Danish dementia (FDD) in humans. To model FDD in animal systems, a knock-in approach was recently implemented in mice expressing a wild-type and mutant allele, which bears the FDD-associated mutation. Since these FDD(KI) mice show behavioural alterations and impaired synaptic function, we c...

Familial British Dementia (FBD) is caused by an autosomal dominant mutation in the BRI2/ITM2B gene (Vidal et al., 1999). FBD(KI) mice are a model of FBD that is genetically congruous to the human disease, because they carry one mutant and one wild-type Bri2/Itm2b allele. Analysis of these mice has shown that the British mutation causes memory impai...