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Rigotto, Giulia (2018) Study of mitochondria physiology in transgenic mouse models of Alzheimer's disease. [Ph.D. thesis]

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Abstract (english)

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the most frequent form of dementia in developed countries, which leads to severe loss of memory and cognitive dysfunctions.
By far, the majority of AD cases are sporadic (SAD), with unknown etiology, for which the main risk factors are represented by aging and by the presence of the allelic variant APO-e4 of apolipoprotein E. Only a small but significant percentage of cases, collectively called familial AD (FAD), is inherited and is caused by autosomal dominant mutations in the genes coding for the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) respectively.
APP is a single transmembrane domain protein with a large extracellular domain, expressed at high level in the brain. PSs are homologous membrane proteins specially localized in the endoplasmic reticulum (ER) and Golgi apparatus; they represent the essential components of the gamma-secretase complex, which, by cleaving APP in concert with beta-secretase, leads to the production of the neurotoxic beta-amyloid peptides.
The identification of these genetic factors involved in FAD cases, allowed the development of transgenic mouse models. Given that SAD and FAD cases are morphologically and clinically similar, these models represent an important research tool to investigate potential common molecular mechanisms between the two AD forms, with the aim of devising effective therapies.
In these studies, two transgenic mouse models were used to perform the experiments. The first one is a single transgenic line, homozygous for the FAD-linked PS2-N141I mutation, which is under the prion promoter control and it is ubiquitously expressed. The second model is a double transgenic line homozygous for both the FAD-linked PS2-N141I mutation and APPSwe mutation, which is under Thy.1 promoter control, thus expressed only in neurons.
We investigated the possible, early impairment of mitochondrial functions in the brain of the transgenic animals. Mitochondria are cytoplasmic organelles responsible for most of the energy supplied to the cells through ATP production; furthermore, they are involved in many other roles, such as Ca2+ homeostasis, reactive oxygen species production (ROS) and apoptosis.
It is well established that mitochondrial impairment contributes to normal aging and to a wide spectrum of age-related diseases, including neurodegenerative diseases, such as AD, Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington’s Disease (HD).
First of all, we started with mitochondria isolated from the brain of WT, single and double transgenic mice of different ages, from neonatal up to 2 years old animals, to investigate the age-dependent progression in the onset of potential mitochondrial dysfunctions.
We evaluated mitochondrial bioenergetics parameters such as the oxygen consumption rate (OCR), the membrane potential and the calcium retention capacity (CRC). These experiments didn’t reveal overt defects in the respiratory complexes activity or in the sensitivity of the permeability transition pore (PTP) to matrix Ca2+ overload in transgenic animals compared to WT, suggesting that these FAD-linked mutations do not cause severe primary defects on the organelles.
Isolated mitochondria represent a useful tool in many instances, but being removed from the cellular environment do not allow the study of the complex interaction that mitochondria entertain with other organelles or components of the cell. For this reason, we decided to study mitochondria in primary hippocampal cultures, specifically because the hippocampus is one of the first and main affected brain areas in AD.
In the context of intact cells, the basal respiration and the ATP synthesis coupled respiration measured by the mean of the Extracellular Flux Analyzer (Seahorse) didn’t show significant differences among the three genotypes, whereas the maximal respiration was significantly higher in WT neurons compared to PS2APP neurons, suggesting a possible impairment in the supply of substrates to mitochondria.
Measuring the ability of mitochondria to sustain the membrane potential upon the selective inhibition of either the respiratory chain or the ATP synthase suggested the presence of a possible defect in the latter enzyme, in its ability to hydrolyze ATP, or the presence of an unknown metabolic defect/s limiting the supply of ATP to the synthase to sustain its reverse activity. Despite these interesting data obtained in hippocampal neurons, we didn’t observe the same strong differences under similar conditions in experiments performed in human fibroblast carrying the same FAD-linked PS2 mutation.
These differences could be due to the fact that fibroblasts are mostly glycolytic cells, which might be less affected than neurons by mitochondrial dysfunctions.
In order to check the ATP synthase reverse activity, we measured NADH oxidation in isolated mouse brain-cortex mitochondria. The preliminary results showed a higher ATP hydrolysis rate in PS2 and PS2APP mitochondria compared with WT, but more experiments are needed to assess the statistical significance of this finding.
Blocking the respiratory chain, or the ATP synthase, in neuronal cells, so likely impairing ATP production, didn't show any major difference in the ability of the cells to handle potentially threatening increased cytosolic calcium concentration, [Ca2+]c. This evidence prompted the conclusion that under these experimental conditions, neurons seem to be equally able to handle a decrease in ATP content, and perhaps prolonged and stronger stimuli would be necessary to disclose possible defects.
Moreover, the basal ROS production in these cells is very low and seems to be similar among the genotypes.
Given the results collected so far, it would be interesting to better clarify the activity of the ATP synthase in the transgenic animals and investigate further the metabolic cross-talk between mitochondria and the rest of the cell.

Abstract (italian)

Il morbo di Alzheimer è la malattia neurodegenerativa più diffusa e una delle principali cause di demenza nei paesi occidentali. Questa patologia determina progressivi danni alla memoria e ad altre importanti funzioni cognitive. La maggior parte dei casi di Alzheimer è sporadica, compare in tarda età e i fattori di rischio più conosciuti sono l’invecchiamento e la variante allelica APO-e4 del gene che codifica per la lipoproteina E. Esiste tuttavia una piccola ma significativa percentuale di casi ereditari (forma familiare di Alzheimer, FAD) che è causata da mutazioni autosomiche dominanti in tre geni che codificano per la Proteina Precursore dell’Amiloide (APP), per la Presenilina-1 (PS1) e la Presenilina-2 (PS2).
L’APP è una proteina transmembrana espressa principalmente nel cervello. Le preseniline sono proteine omologhe di membrana presenti soprattutto nel reticolo endoplasmatico e nell’apparato di Golgi. Costituiscono ciascuna, indipendentemente, la parte catalitica dell’enzima gamma-secretasi che, insieme all’enzima beta-secretasi, è responsabile del taglio dell’APP e della conseguente formazione di peptidi Abeta, molto dannosi per il cervello.
L’identificazione di mutazioni genetiche coinvolte nelle forme familiari di Alzheimer, ha permesso lo sviluppo di modelli di topi transgenici. Dato che i casi sporadici e quelli familiari della malattia sono clinicamente molto simili, questi modelli rappresentano uno strumento essenziale per la ricerca, poiché permettono lo studio di possibili meccanismi molecolari condivisi e danno la possibilità di scoprire/migliorare eventuali terapie. In questo progetto, gli esperimenti sono stati effettuati utilizzando due modelli transgenici di topi disponibili in laboratorio.
Il primo è un topo transgenico omozigote per la mutazione PS2-N141 che è stata posta sotto il controllo del promotore prionico e quindi viene espressa in tutti i tessuti. Il secondo modello è omozigote per la stessa mutazione di PS2 e anche per una mutazione dell’APP (APPSwe) che si trova sotto il controllo del promotore Thy.1, ed è quindi espressa solo nel cervello.
L’obiettivo di questo studio è quello di trovare possibili danni precoci nei mitocondri di cervello in questi modelli transgenici di Alzheimer. I mitocondri sono organelli citoplasmatici principalmente coinvolti nel fornire energia alla cellula sotto forma di ATP, ma sono in realtà indispensabili per molte altre funzioni, come ad esempio il controllo dell’omeostasi del calcio, la produzione delle specie radicali di ossigeno (ROS) e l’apoptosi. Al giorno d’oggi, è ampiamente accettato che danni a questi organelli non sono solo presenti durante il normale invecchiamento ma anche in molte altre malattie legate ad esso, comprese le malattie neurodegenerative come l’Alzheimer, il morbo di Parkinson, la sclerosi laterale amiotrofica e la corea di Huntington.
I primi esperimenti sono stati effettuati in mitocondri isolati dal cervello dei topi WT, PS2 e PS2APP, partendo da quelli di 8 giorni fino a topi di 2 anni, per documentare la possibile presenza e/o progressione di disfunzionalità dei mitocondri. Abbiamo valutato diversi parametri bioenergetici, come la velocità di consumo dell’ossigeno (oxygen consumption rate, OCR), il potenziale di membrana mitocondriale e la capacità dei mitocondri di accumulare calcio nella matrice (calcium retention capacity, CRC). I risultati di questi esperimenti non hanno tuttavia rivelato particolari differenze tra i topi WT e quelli transgenici, né per quanto riguarda l’attività dei complessi della catena respiratoria, né per la sensibilità del poro di transizione della permeabilità mitocondriale (permeability transition pore, PTP) ad un elevato aumento di Ca2+ nella matrice. Tali dati suggeriscono che probabilmente, queste mutazioni FAD non inducono direttamente danni ai mitocondri.
I mitocondri isolati sono uno strumento molto utile per studiare le caratteristiche e la funzionalità di questi organelli, ma presentano tuttavia alcuni svantaggi: per esempio, in queste condizioni il mitocondrio è separato dal suo ambiente fisiologico e non è così possibile studiare le sue interazioni con le altre componenti del citoplasma. Per questo motivo, abbiamo deciso di spostare la nostra attenzione sulle colture primarie neuronali di ippocampo, perché quest’area del cervello è una delle regioni maggiormente e precocemente colpite dall’Alzheimer.
Per prima cosa, abbiamo comparato la respirazione basale e la respirazione accoppiata alla sintesi di ATP misurate con l’Extracellular Flux Analyzer (Seahorse) senza però trovare differenze significative tra le colture dei tre genotipi. La misura della respirazione massima è invece più alta nei WT rispetto a PS2 e PS2APP, e la differenza è significativa tra WT e PS2APP, suggerendo una possibile alterazione nel rifornimento di substrati ossidabili ai mitocondri.
In seguito, le misure effettuate per valutare la capacità dei mitocondri di mantenere il potenziale di membrana dopo l’inibizione selettiva dei complessi della catena respiratoria o dell’ATP sintasi, hanno rivelato un possibile difetto in quest’ultima, che potrebbe limitare la capacità di idrolizzare l’ATP, oppure alla presenza di difetti metabolici sconosciuti che limitano il rifornimento di ATP del citoplasma per sostenere l’attività idrolitica. Visti questi risultati, abbiamo provato a ripetere gli esperimenti in fibroblasti provenienti da pazienti caratterizzati dalla stessa mutazione di PS2 presente nei modelli transgenici di topo. In questo caso però, la differenza tra fibroblasti provenienti da controlli sani e quelli provenienti dai pazienti non è così marcata come quelli emersi dagli studi nelle colture neuronali primarie. Questo può essere spiegato dal fatto che i fibroblasti sono cellule molto diverse dai neuroni, potrebbero ad esempio utilizzare di più la glicolisi, o semplicemente potrebbero risentire meno dell’effetto della mutazione in PS2.
Per verificare se effettivamente potesse esserci un difetto a livello dell’attività idrolitica dell’ATP sintasi, abbiamo provato a misurare indirettamente la velocità di idrolisi dell’ATP in mitocondri isolati da cervello di topi dei tre genotipi tramite l’ossidazione del NADH. Al momento, sembra che la velocità di idrolisi sia più veloce nei transgenici, anche se il numero di esperimenti non è ancora sufficiente per stabilire se tale differenza sia significativa o meno.
Abbiamo inoltre verificato che bloccando la catena respiratoria o l’ATP sintasi, di fatto diminuendo la quota di ATP prodotto dai mitocondri, i neuroni WT, PS2 e PS2APP sono ugualmente in grado di regolare il calcio citosolico. Questo suggerisce che in queste condizioni sperimentali i neuroni sono in grado di sopperire alla riduzione dell'ATP e che probabilmente per evidenziare delle differenze tra i genotipi bisognerebbe utilizzare uno stimolo più forte o prolungato.
Un altro parametro verificato è la produzione di ROS, che in condizioni basali è molto basso e che sembra essere simile tra i genotipi.
Dati i risultati ottenuti fino ad adesso, sarebbe interessante studiare nel dettaglio l’attività dell’ATP sintasi che potrebbe essere alterata nei modelli transgenici e soprattutto potrebbe essere interessante studiare le interazioni metaboliche tra i mitocondri e il resto della cellula.


EPrint type:Ph.D. thesis
Tutor:Pozzan, Tullio
Ph.D. course:Ciclo 30 > Corsi 30 > SCIENZE BIOMEDICHE SPERIMENTALI
Data di deposito della tesi:14 January 2018
Anno di Pubblicazione:14 January 2018
Key Words:fisiologia mitocondriale/mitochondria physiology, malattia di Alzheimer/Alzheimer's disease, potenziale di membrana mitocondriale/mitochondrial membrane potential, neuroni/neurons, ippocampo/hippocampus, velocità di cosumo dell'ossigeno/oxygen consumption rate
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/12 Biochimica clinica e biologia molecolare clinica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:10862
Depositato il:15 Nov 2018 12:34
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