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Alzheimer’s Disease

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Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease

Part of the book series: Subcellular Biochemistry ((SCBI,volume 65))

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aβ) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons. According to the amyloid hypothesis of AD, the overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Genetic, age-related and environmental factors contribute to a metabolic shift favoring the amyloidogenic processing of APP in detriment of the physiological, secretory pathway. Aβ peptides are generated by the successive cleavage of APP by beta-secretase (BACE-1) and gamma-secretase, which has been recently characterized as part of the presenilin complex. Among several beta-amyloid isoforms that bear subtle differences depending on the number of C-terminal amino acids, Aβ 1−42 plays a pivotal role in the pathogenesis of AD. The neurotoxic potential of the Aβ peptide results from its biochemical properties that favor aggregation into insoluble oligomers and protofibrils. These further originate fibrillary Aβ species that accumulate into senile and neuritic plaques. These processes, along with a reduction of Aβ clearance from the brain, leads to the extracellular accumulation of Aβ, and the subsequent activation of neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and cellular death. Intracerebral amyloidosis develops in AD patients in an age-dependent manner, but recent evidence indicate that it may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age, and highest estimates in old age. According to recent propositions, three clinical phases of Alzheimer’s disease may be defined: (i) pre-symptomatic (or pre-clinical) AD, which may last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade; (ii) pre-dementia phase of AD (compatible with the definition of progressive, amnestic mild cognitive impairment), in which early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve; (iii) clinically defined dementia phase of AD, in which cognitive and functional impairment is severe enough to surmount the dementia threshold; at this stage there is significant accumulation of neuritic plaques and neurofibrillary tangles in affected brain areas, bearing relationship with the magnitude of global impairment. New technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid may depict correlates of intracerebral amyloidosis in individuals with mild, pre-dementia symptoms. These methods are commonly referred to as AD-related biomarkers, and the combination of clinical and biological information yields good diagnostic accuracy to identify individuals at high risk of AD. In other words, the characterization of pathogenic Aβ by means of biochemical analysis of biological fluids or by molecular neuroimaging are presented as diagnostic tools to help identify AD cases at the earliest stages of the disease process. The relevance of this early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are more likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Therapies targeting the modification of amyloid-related cascades may be viewed as promising strategies to attenuate or even to prevent dementia. Therefore, the cumulative knowledge on the pathogenesis of AD derived from basic science models will hopefully be translated into clinical practice in the forthcoming years.

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Abbreviations

APP :

Amyloid Precursor Protein

AD:

Alzheimer’s Disease

APOE:

Apolipoprotein E

Aβ :

Amyloid-β peptide

CaMK-ll:

Calcium calmodulin-kinase ll

CDK5:

Cyclin-Dependent Kinases 5

CERAD:

Consortium to Establish a Registry for Alzheimer’s Disease

CNS:

Central Nervous System

CSF:

Cerebrospinal fluid

ER:

Endoplasmic Reticulum

GSK3β :

Glycogen Synthase Kinase-3β

IDE:

Insulin-Degrading Enzyme

MAPK:

Microtubule Associated Protein Kinases

MCI:

Mild Cognitive Impairment

NFT:

Neurofibrillary Tangle

NIA:

National Institute of Aging

PHF:

Paired Helicoidal Filaments

PKA:

Protein Kinase A

PKC:

Protein Kinase C

PP:

Phosphatases Protein

P-Tau:

Phosphorylated Tau

sAPPα :

Soluble N-terminal fragment

TGN:

Trans-Golgi Network

T-Tau:

Total Tau

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  1. Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos 785, Terceiro Andar-Ala Norte, 05403-010, São Paulo-SP, Brazil

    Vanessa J. De-Paula, Marcia Radanovic, Breno S. Diniz & Orestes V. Forlenza

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  1. Vanessa J. De-Paula
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  2. Marcia Radanovic
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  3. Breno S. Diniz
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  4. Orestes V. Forlenza
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Correspondence to Orestes V. Forlenza .

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  1. Inst. of Zoology, University of Mainz, Becherweg 6, Mainz, 55099, Germany

    J. Robin Harris

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De-Paula, V.J., Radanovic, M., Diniz, B., Forlenza, O. (2012). Alzheimer’s Disease. In: Harris, J. (eds) Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease. Subcellular Biochemistry, vol 65. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5416-4_14

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