Adrenomedullin, a new therapeutic target for the treatment of Alzheimer's disease

One of the consequences of the ageing world population is the increase in neurodegenerative diseases such as Alzheimer s or frontotemporal dementia. Neurodegenerative diseases are pathologies characterized by a gradual and irreversible deterioration of neurons and presenting with different neurological syndromes depending on the affected brain area. Dementias are the most common neurodegenerative disorders, for which therapeutic options are very limited and merely symptomatic, rather than neuroprotective or neuroregenerative. Furthermore, the most common dementia disorders, Alzheimer s disease or frontotemporal dementia, affect over 7 million people in Europe, and this figure is expected to double every 20 years as the population ages. The estimated care costs for dementia in Europe are approximately 130 billion per year, which cause a big concern on public health systems. Together with this, there is also an enormous social and human burden on patients as well as caregivers. For this reasons, one of the major challenges faced by neuroscience research field is to bring more insights into the molecular pathomechanisms that underlie the neurodegenerative processes in dementia disorders in order to design novel pharmacological approaches and develop successful therapies for preventing or treating dementia. The cytoskeleton plays an essential role on many fundamental neuronal processes, such as neuronal migration, cargo transport, polarity, and differentiation. Perturbations in the architecture of cytoskeleton can result in the loss of neuronal functions leading to neurodegeneration. This thesis aims to study the role of alterations in the cytoskeleton in the pathogenesis of neurodegenerative diseases. In particular, the thesis will focus on the involvement of adrenomedullin in alterations of the cytoskeleton and its relationship with two of the most common dementias, Alzheimer s disease and frontotemporal dementia. First, an overview of the current status of adrenomedullin, with special focus on its interaction with the cytoskeleton, along with a summary of the most relevant neurodegenerative diseases and the different possible pathways by which adrenomedullin might mediate its actions will be provided in the Chapter I, Introduction. Chapter II describes the hypothesis and objectives of the present thesis. Chapter III presents a study on the involvement of adrenomedullin in Alzheimer s disease and the purported mechanism of action by which adrenomedullin exert its effects in the course of the disease. Chapter IV describes changes in adrenomedullin expression in the ageing brain. In addition, it is described in this chapter the effects on cognition of deleting adrenomedullin gene in the CNS (AMKO mouse model) and the effects of ageing in this model. Chapter V presents a brief study on the involvement of adrenomedullin alterations on frontotemporal dementia and the possible influence on cytoskeleton. Finally, Chapter VI, General Discussion, integrates and highlights the most relevant aspects of the previous chapters, to end with the Chapter VII, Conclusions, summarising the main findings of the present thesis

Adrenomedullin, a novel target for neurodegenerative diseases

Neurodegenerative diseases represent a heterogeneous group of disorders whose common characteristic is the progressive degeneration of neuronal structure and function. Although much knowledge has been accumulated on the pathophysiology of neurodegenerative diseases over the years, more efforts are needed to understand the processes that underlie these diseases and hence to propose new treatments. Adrenomedullin (AM) is a multifunctional peptide involved in vasodilation, hormone secretion, antimicrobial defense, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins that interfere with microtubule dynamics. Furthermore, AM may intervene in neuronal dysfunction through other mechanisms such as immune and inflammatory response, apoptosis, or calcium dyshomeostasis. Alterations in AM expression have been described in neurodegenerative processes such as Alzheimer’s disease or vascular dementia. This review addresses the current state of knowledge on AM and its possible implication in neurodegenerative diseases

Reduced adrenomedullin parallels microtubule dismantlement in frontotemporal lobar degeneration

Tau is a microtubule-associated protein highly expressed in neurons with a chief role in microtubule dynamics and axonal maintenance. Adrenomedullin gene (ADM) codifies for various peptides that exert broad range of actions in the body. Previous works in our groups have shown that increased ADM products are positively correlated to microtubule disruption and tau pathology in Alzheimer's disease brains. In the present study, we explore the involvement of ADM in the neuropathology of frontotemporal lobar degeneration that presents with primary tauopathy (FTLD-tau). Proteins from frontal cortices of FTLD-tau patients and age- and sex-matched non-demented controls were analyzed with antibodies against different microtubule components, including adrenomedullin, and synaptic markers. Tau pathology in frontal cortex from FTLD patients was confirmed. Levels of total βIII-tubulin as well as acetylated and detyrosinated tubulins, two markers of stabilized and aged microtubules, were significantly reduced and directly correlated with PSD95 and proBDNF in FTLD-tau patients when compared to non-demented controls. In contrast, no change in actin cytoskeleton was found. Interestingly, changes in microtubule elements, indicators of disturbed axonal preservation, were accompanied by decreased levels of free adrenomedullin, although no association was found. Altogether, reduced levels of adrenomedullin might not be directly linked to the microtubule pathology of FTLD-tau, but based on previous works, it is suggested that downregulation of ADM might be an adaptive attempt of neurons to mitigate microtubule disruption

Increased levels of brain adrenomedullin in the neuropathology of Alzheimer's Disease

Alzheimer's disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD