Alzheimer's Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of A? peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal fragment, ?-CTF, which is then processed into several A? isoforms by ?-secretase. Genetic data suggest that regulation of APP processing contributes to AD, which lead us to perform genetic screens for regulators of APP processing. We isolated ITM2B/BRI2, a gene mutated in AD-like familial Danish and British dementias (FDD and FBD), and found that it tightly binds APP and inhibits its cleavage by BACE1. To address the hypothesis that alterations of APP processing participate in dementia we generated knock-in models of Danish and British dementias. These FDDKI and FBDKI mice showed synaptic plasticity/memory deficits due to loss of BRI2 function and increased processing of APP by BACE1. Surprisingly however, we found that ?-CTF and not A?,is the main synaptotoxic APP metabolite in these mice. The simplest explanation of our observations is that AD and FDD/FBD are pathogenically different. Alternatively, our observation may reflect the model systems we use. The pathogenic centrality of A? has been shown in mouse models over-expressing mutant forms of human AD-associated genes (APP and PS) and thus human A?, whereas our results stem from model systems that rely on endogenous, murine APP expression coupled to loss of an APP processing regulator. In this context, it is important to note that ITM2B/BRI2 has been recently identified as a master regulator of the common patterns of gene expression shared by healthy ApoE4 carriers and LOAD patients who do not carry the ApoE4 allele. This evidence establishes a direct connection in humans between ITM2B/BRI2 and ApoE4, the strongest genetic risk factor for AD, as well as ITM2B/BRI2 and sporadic AD, supporting the idea that FDD and FBD are genetic variants of FAD. Regardless of which explanation is correct, two points are worth noting; 1) a therapeutic approach inhibiting BACE1 cleavage of APP would be efficacious in all scenarios; 2) ?-secretase inhibition, an aggressively sought-after therapeutic approach for AD, would result in accumulation of ?-CTF so it is vital to determine if this intermediate contributes to pathogenesis. In this application, we will further characterize the mechanisms by which APP processing mediates memory deficit. These studies are likely to shed light on the pathogenesis of AD, as well as to unveil novel targets for disease-modifying AD drugs.

Public Health Relevance

Mutations in genes that regulate the processing of APP cause Familial Dementias in humans. BRI2 is one of these genes. We have generated a mouse model that faithfully represents the human dementias caused by the mutation in BRI2. In addition, we have also generated mice in which we can inactivate BRI2 in the brain of adult mice. The mice we made have shown that when BRI2 is mutated or eliminated, APP processing is increased and causes memory loss. The models of Danish and British dementia that we made reproduce accurately the genetic defects of patients. Therefore, they are ideal systems to dissect the pathogenic mechanisms that cause dementia in humans and to test therapies for human dementias, including Alzheimer's disease. These studies will also serve as a proof of concept to development BRI2-like drugs that reduce APP processing without inhibiting the enzymes that mediate processing of APP.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG033007-10
Application #
9607219
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2018-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
Biundo, F; d'Abramo, C; Tambini, M D et al. (2017) Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations. Transl Psychiatry 7:e1198
Del Prete, Dolores; Rice, Richard C; Rajadhyaksha, Anjali M et al. (2016) Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration. J Biol Chem 291:17209-27
Fá, M; Puzzo, D; Piacentini, R et al. (2016) Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory. Sci Rep 6:19393
Biundo, Fabrizio; Ishiwari, Keita; Del Prete, Dolores et al. (2015) Interaction of ApoE3 and ApoE4 isoforms with an ITM2b/BRI2 mutation linked to the Alzheimer disease-like Danish dementia: Effects on learning and memory. Neurobiol Learn Mem 126:18-30
Fanutza, Tomas; Del Prete, Dolores; Ford, Michael J et al. (2015) APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses. Elife 4:e09743
Del Prete, Dolores; Lombino, Franco; Liu, Xinran et al. (2014) APP is cleaved by Bace1 in pre-synaptic vesicles and establishes a pre-synaptic interactome, via its intracellular domain, with molecular complexes that regulate pre-synaptic vesicles functions. PLoS One 9:e108576
D'Adamio, Luciano; Castillo, Pablo E (2013) Presenilin-ryanodine receptor connection. Proc Natl Acad Sci U S A 110:14825-6
Lombino, Franco; Biundo, Fabrizio; Tamayev, Robert et al. (2013) An intracellular threonine of amyloid-? precursor protein mediates synaptic plasticity deficits and memory loss. PLoS One 8:e57120
Matrone, Carmela; Luvisetto, Siro; La Rosa, Luca R et al. (2012) Tyr682 in the A?-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. Aging Cell 11:1084-93
Tamayev, Robert; D'Adamio, Luciano (2012) Inhibition of ?-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. Mol Neurodegener 7:19

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