Wednesday · Oct 7
9:00 - 11:00

Amyloid β Peptide, Tau aProtein, NGF Metabolism. Early Biomarkers and Associated Mechanisms in Alzheimer´s Diseasec

Diana Jerusalinsky


Tomas Falzone


Alzheimer´s disease (AD) is a major neurodegenerative disorder with two forms: the familial, with genetic mutations, and the sporadic affecting people over 65. AD is one of the biggest unresolved health burdens with life expectancy increase. Amyloid β (Aβ) peptide deposition may begin 20 years before and neurobrillary degeneration could be present 10 years prior to onset of memory loss. The finding of AD biomarkers has enabled a molecular definition of AD: ATN (Amyloid, Tau, Neurodegeneration). This Symposium is aimed to show different approaches to analyze relevant biomolecules roles, as from Aβ effect in neurodevelopment and neurodegeneration, artificial humanized organoids to analyze changes in axonal transport involving tau protein, the NGF metabolism as a preclinical AD signal evidenced in body fluids, to finalize with biomarkers imaging and associated cognitive impairments in patients, to discuss and interpret molecular and metabolic mechanisms and their relationship with early biomarkers associated to pre-Dementia stages. There will be four lectures: 1) Amyloid beta oligomers in neural development and degeneration 2) From balanced axonal transport in health, to impaired dynamics in human models of tauopathies: untangling the road to neurodegeneration. 3) The deregulation of the NGF metabolism is present as from preclinical AD and it is revealed in body fluids. 4) Cognitive studies and biomarkers in predementia stages of patients with AD.

Amyloid beta oligomers in neural development and degeneration

William Klein

Departments of Neurobiology and Neurology, Northwestern University

Human amyloid beta (Aβ42) is unusually prone to self-association, and its oligomers manifest a gain-of-function neurotoxicity. Evidence strongly indicates that soluble Aβ oligomers (AβOs), not amyloid plaques, are the pathogenic form of Aβ in Alzheimer’s disease (AD). AβOs manifest in an AD-dependent manner in humans and animal models. Experimentally, they induce memory dysfunction and multiple facets of AD neuropathology. Evolutionary retention of the toxin-forming Aβ sequence is surprising but could be explained if, under some circumstances, AβOs were essential to neural function. Supporting this idea, we have discovered that AβOs are transiently expressed in the developing retina of chick (which has an Aβ sequence identical to humans) and are required for proper cell placement. AβOs appear first in the optic nerve layer, spread outward into specific cell bodies and synaptic layers, then down-regulate, with low expression remaining near photoreceptors. AβO expression is like a molecular wave progressing across the retina, virtually disappearing when circuitry has been established. Intravitreal injections of BACE inhibitor or AβO antibody during development cause disrupted nerve cell placement and formation of retina folds as found in various pathological conditions. AβOs thus constitute a new type of peptidergic hormone with a critical short-lived role in CNS development, suggesting AβO presence in AD may be a pathological reprise of a role played in neural development.

From balanced axonal transport in health, to impaired dynamics in human models of tauopathies: untangling the road to neurodegeneration.

Tomas Falzone


The microtubule associated protein Tau undergoes many pos-translational modifications such as a tight developmental regulation of balanced 3R-4R tau isoform expression in the human nervous system. Tau protein dysfunction is a key step in the process leading to neurodegeneration in tauopathies and its imbalance, due to overexpression or either towards 3R or 4R tau isoforms, has been closely associated with disease. While some disease hypotheses are focused on the toxic gain of function of abnormal tau aggregates, others propose that tau loss of function properties are involved in triggering neuronal death. Different studies have unlocked new functional roles for tau in neuronal homeostasis that range from the regulation of axonal transport dynamics to the modulation of neuron electrical properties. However, little is known on how tau isoform balance or tau protein levels exert a regulation over these critical cellular functions. We have modulated tau isoforms or its expression levels in human derived neurons to unravel the molecular pathways in which tau control axonal transport. Our work supports the role of tau in the tight control of intrinsic neuronal phenotypes such as the regulation of molecular motor activity in axonal transport making it relevant for understanding neuronal dysfunction that can lead to disease.

The deregulation of the NGF metabolism is present as from preclinical Alzheimer’s disease and it is revealed in body fluids.

A. Claudio Cuello

Department of Pharmacology and Therapeutics, McGill University; Visiting Professor, Oxford University

Our laboratory (Bruno and Cuello, PNAS, 2006) discovered a novel NGF metabolic pathway demonstrating that proNGF is released in an activity-dependent manner and converted to mature NGF (mNGF) in the extracellular space and that the remaining, receptor-unbound mNGF, is ultimately degraded by metalloproteases. This pathway has been validated pharmacologically and shown to be compromised in Alzheimer’s and in Down syndrome. More recently, we have found that the deregulation of the NGF metabolism is already present in DS at AD pre-symptomatic stages (Iulita et al Alz&Dementia 2016) and more recently found deregulated in the brains of non-cognitively impaired bearing asymptomatic AD pathology (Pentz et al, Mol. Psychiatry, 2020). The deregulation of the NGF pathway could reveal “silent” (preclinical) AD pathology. We found that incremental levels of plasma proNGF in DS individuals in transition from DS-AD asymptomatic to DS-AD symptomatic predicted a severe subsequent cognitive deterioration (Iulita et al, Alz&Dementia 2016). A deregulation more faithfully revealed in the cerebrospinal fluid from DS AD asymptomatic and symptomatic (Pentz et al, unpublished). CONCLUSIONS The above observations indicate that the investigation of levels of key molecules of NGF metabolic pathway in plasma and in cerebrospinal fluids offers an opportunity to reveal the ongoing, silent, preclinical Alzheimer’s pathology as well as to facilitate preclinical AD therapeutic interventions.

Cognitive studies and biomarkers in predementia stage of patients with Alzheimer Disease

Ricardo Allegri

Instituto Neurológico Fleni

The main pathophysiological mechanism underlying Alzheimer’s disease (AD) involves extracellular amyloid deposits and neurofibrillary degeneration secondary to abnormal tau protein hyperphosphorylation. AD is present many years before symptoms develop. Bateman et al. detected amyloid deposits over 20 years, and neurofibrillary degeneration over 10 years, prior to the onset of clinical symptoms. Prior to the development of the AD biomarker, clinical diagnosis was identified as either possible or probable, and definite diagnosis needed to be confirmed by post-mortem brain tissue histopathology The discovery of AD biomarkers gave rise to a new paradigm in relation to degenerative dementias. The biomarker assay allows in vivo assessment of pathophysiological disease traits. Current biomarkers used in clinic for AD include: Aβ1-42, total tau and phosphorylated tau assay in cerebrospinal fluid (CSF), tructural neuroimaging studies such as brain magnetic resonance imaging (MRI) and hippocampal volume analysis, functional neuroimaging of metabolic activity such as fluorodesoxyglucose (FDG ) positron emission tomography (PET) and Protein-identifying neuroimaging using amyloid and tau PET. We like to describe our experience in clinical practice with the use of biomarkers in predementia stages of patients with Alzheimer Disease and the future with the next blood AD biomarkers.