Recent Advances in Alzheimer Research

In behavioural neurosciences, animal models are aimed at providing insights into normal and pathological human behaviour and its underlying neuronal processes. Alzheimerʼs disease (AD) is the most common origin of dementia in the elderly. Several factors have been identified, such as the amyloid precursor protein (APP), hyperphosphorylation of tau protein, and the secretase enzymes. Animal models are important for elucidation of mechanistic aspects of AD. Transgenic models recapitulate expression of human β-APP and tau hyperphosphorylation to understand the pathogenesis of AD. In this chapter, some animal models are reviewed and discussed briefly in order to elucidate some criteria that an animal model should fulfil to mimic human neurodegenerative diseases.

A normal development of the central nervous system is an essential process to a healthy the adult brain. After birth, some brain areas are still maturating and, even in the adulthood, the brain networks are in constant reorganization. The physiological and morphological changes that occur during nervous system maturation can be the key to the insurgence of neurodegenerative diseases such Alzheimer’s disease (AD). AD is the most common cause of severe cognitive decline in elderly. The set of neuronal morphological changes presented even before clinical symptoms onset is strongly correlated with future cognitive impairments. However, it is not clear yet which morphofunctional features are more accurate to distinguish the healthy and the abnormal brain as well as its future susceptibility in developing AD. In this chapter, we described the neuroanatomic aspects of AD. Specifically, we focused on the progression of affected areas throughout AD stages and on the selective aspects that make several neuronal populations and brain areas more vulnerable to pathological changes. External and internal factors that might influence morphological features are also addressed. While intrinsic characteristics such as myelination and pigmentation could help to predict the pattern of anatomic advance of AD, on the other hand, cognitive reserve is an example of how external input and lifestyle can delay the appearance of clinical symptoms even when morphologic changes are already pronounced. The early diagnosis and staging are fundamental steps to provide information for more specific therapeutic approaches. Ultimately, some of the advances and techniques for this challenging diagnosis are also detailed.

Biological membranes are a vital component of all living cells. They consist mainly of lipids and proteins. The proteins are embedded into the lipid structure, whose distribution in an aqueous environment forms a bilayer. The biological membranes have an average thickness of 30Å, determined by the size of the carbon chain of lipids, which range from 14 to 24 carbons. The lipid portion of biological membranes is also fundamental to determine their physicochemical properties such as membrane order, fluidity, and hydrophobicity. As Alzheimer’s disease pathology is mainly due to actions of Aβ peptides on the plasma membrane, its modifications are of great importance. In fact, membrane lipids, such as cholesterol, ceramides, gangliosides, and fatty acids, have been implicated in the molecular mechanisms of various stages of Alzheimer’s disease pathology. The following chapter describes the main changes in membrane lipid composition in Alzheimer’s disease (AD).

It is estimated that 44 millions of people have Alzheimer’s disease (AD) or related dementia around the world. The AD is an irreversible progressive brain disorder that destroys the memory and thinking and causes the loss of cognitive functions. The development of AD is strongly correlated with the development of plaques and tangles in the brain. Beta-amyloid (Aβ) peptides are the main compound in the brain plaques however, their neurotoxic effects remain unclear. These peptides are generated from Amyloid Precursor Protein (APP) and the APP processing may be modulated by many factors, such as lipid rafts. Aβ coexists in different forms in the brain and the exact neurotoxic effect of each one is not understood. The majority of the studies about Aβ neurotoxicity suggests that the fibrillar form is the most neurotoxic and for this reason, much effort has been employed to understand mechanisms that modulate or inhibit the fibrillation process. Other studies suggest that the main neurotoxic form is the oligomer, which forms channels in the lipid membrane and induces cell death. In this chapter, we explore the mechanism of Aβ’s production and fibrillation, and the factors that can modulate it.

The maintenance of intracellular trafficking is essential to neuron survival. Well-organized intracellular events contribute to synapse effectiveness and efficient communication between cells. Changes in microtubule trackers, vesicles, mitochondria or autophagosomes can lead to neurodegeneration. Protein aggregates containing amyloid-beta peptides and hyperphosphorylated tau are hallmarks of Alzheimer’s disease and they impair intracellular trafficking. Moreover, dysfunction of intracellular transport might increase the formation of protein aggregates. In this chapter it is discussed the association between intracellular trafficking and Alzheimer’s disease with emphasis in protein aggregation, cholesterol transport, molecular motors, rab proteins, autophagy, endoplasmic reticulum, mitochondria and calcium homeostasis.

Alzheimer's disease is a neurodegenerative disorder with no cure and not completely understood mechanisms. This devastating disease is one of the main causes of dementia in elderly people worldwide. Among different mechanisms of neuronal death associated to Alzheimer's disease, oxidative stress can be considered as one of the most studied. Several data from literature in this field have shown that oxidative stress seems to be a critical step in the neurodegenerative course of the disease. Clinical trials using antioxidants have described conflicting results, some of them supporting the importance of the use of antioxidant compounds to ameliorate disease's symptoms and the others showing negative results in terms of beneficial effects of antioxidant therapy in the disease progression.

The first ideas proposed by Zaven Khachaturian about the calcium (Ca2+) hypothesis of brain aging foster researchers into cellular and molecular mechanisms trying to explain Ca2+ alterations of brain function and cognitive deficits. Alzheimer’s disease (AD) is dementia causally linked to aging, therefore Ca2+ cellular processes underlying aging-related impairments in the brain may share similarities to severe dementia, as in AD. The effective control of cytosolic Ca2+ is essential for the modulation of various processes and pathways of neuronal signaling, and its inefficiency or deregulation can lead to austere pathological conditions. This chapter shows pieces of evidence of Ca2+ deregulation in AD and its consequences, focusing on intrinsic properties of the neurons.