Selective alterations of neurons and circuits related to early memory loss in Alzheimers's disease

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permissionAprogressive loss of episodic memory is awell-known clinical symptom tha tcharacterizes Alzheimer’s disease(AD). The beginning of this loss of memory has been associated with the very early, pathological accumulation of tau and neuronal degeneration observed in the entorhinal lcortex(EC). Tau-related pathology is thought to then spread progressively to the hippocampal formation and other brain areas as the disease progresses.The major cortical afferent source of the hippocampus and dentate gyrus is the EC through the performant pathway. At least two main circuits participate in the connection between EC and the hippocampus; one originating in layer II and the other in layer III of the EC giving rise to the classical trisynaptic (ECII→dentategyrus→CA3→CA1) and mono synaptic (ECIII→CA1) circuits. Thus, the study of the early pathological changes in these circuitsis of great interest. In this review,we will discuss mainly the alterations of the granule cell neurons of the dentate gyrus and the atrophy of CA1 pyramidal neurons that occu rin AD in relation to the possible differential alterations of these two main circuitsThis work wa ssupported by grants from the following entities: CIBERNED,Comunidad de Madrid (grant S2010/BMD-2331), Fundación CIEN, Fundación Ramón Areces and the Spanish Ministry of Economy and Competitiveness (SAF2011-24841, BFU2012-34963 and the Cajal Blue Brain Project, Spanish partner of the Blue Brain Project initiative from EPFL

The ever-changing morphology of hippocampal granule neurons in physiology and pathology.

Newborn neurons are continuously added to the hippocampal dentate gyrus throughout adulthood. In this review, we analyze the maturational stages that newborn granule neurons go through, with a focus on their unique morphological features during each stage under both physiological and pathological circumstances. In addition, the influence of deleterious (such as schizophrenia, stress, Alzheimer’s disease, seizures, stroke, inflammation, dietary deficiencies, or the consumption of drugs of abuse or toxic substances) and neuroprotective (physical exercise and environmental enrichment) stimuli on the maturation of these cells will be examined. Finally, the regulation of this process by proteins involved in neurodegenerative and neurological disorders (such as Glycogen synthase kinase 3β, Disrupted in Schizophrenia 1 (DISC-1), Glucocorticoid receptor, pro-inflammatory mediators, Presenilin-1, Amyloid precursor protein, Cyclin-dependent kinase 5 (CDK5), among others, will be evaluated. Given the recently acquired relevance of the dendritic branch as a functional synaptic unit required for memory storage, a full understanding of the morphological alterations observed in newborn neurons may have important consequences for the prevention and treatment of the cognitive and affective alterations that evolve in conjunction with impaired adult hippocampal neurogenesis

Tau protein and adult hippocampal neurogenesis

Tau protein is a microtubule associated protein found in the axonal compartment that stabilizes neuronal microtubules under normal physiological conditions. Tau metabolism has attracted much attention because of its role in neurodegenerative disorders called tauopathies, mainly Alzheimer disease. Here, we review recent findings suggesting that axonal outgrowth in subgranular zone during adult hippocampal neurogenesis requires a dynamic microtubule network and tau protein facilitates to maintain that dynamic cytoskeleton. Those functions are carried out in part by tau isoform with only three microtubule-binding domains (without exon 10) and by presence of hypherphosphorylated tau forms. Thus, tau is a good marker and a valuable tool to study new axons in adult neurogenesis