Pathophysiology of Alzheimer's Disease
Section snippets
Epidemiology of Alzheimer's disease
The incidence and prevalence of AD rise with increasing age and are higher in women in part because of their increased longevity. The incidence of AD ranges from 1% at ages 65 to 70 to approximately 4% over age 85. In the United States, the number of new cases per year is expected to triple from approximately 420,000 in 2000 to more than 1.3 million in 2050 [1]. Estimates of prevalence of AD range from the lowest figure of 3% of the population at 65 years to the highest reported estimate of 47%
Genetics of Alzheimer's disease
The presence in some families of AD individuals who have an autosomal dominant inheritance pattern has allowed for the discovery of disease genes. Mutations on three genes, known as causative genes, are fully penetrant and cause aggressive forms of early-onset AD. The causative genes are those encoding amyloid precursor protein on chromosome 21q21 (APP), presenilin 1 on chromosome 14q24 (PSEN1), and presenilin 2 on chromosome 1q42 (PSEN2). Mutations in these genes account for approximately 5%
Nongenetic risk factors for Alzheimer's disease
AD is caused by a combination of genetic and environmental factors, and the role of environment cannot be ignored. A lot of effort has been devoted to identifying those specific genetic and environmental factors, determining their relative importance, understanding their interactions, and capitalizing on this knowledge to treat and prevent the disease.
Prevalent pathophysiologic hypothesis: the β-amyloid cascade
Neuritic plaques, the characteristic lesions found in the brain of patients who have AD, are composed mainly of aggregates of a peptide with 40 or 42 amino-acid residues, known as Aβ. The Aβ peptide is the result of the metabolic processing of a complex transmembrane glycoprotein, known as APP. APP may be processed metabolically according to two pathways (Fig. 2). In the so-called “nonamyloidogenic pathway,” the α-secretase enzyme cleaves APP within the Aβ sequence and releases its
Transportation and degradation of β-amyloid
Enormous progress has been achieved in understanding how Aβ is generated from APP and huge pharmacologic efforts have been made in trying to interfere with Aβ production. In the past few years, interest also has been directed to the fate of Aβ once it is generated from APP and the pharmacologic approaches to boost the processes involved in the physiologic clearance of Aβ from the brain. Soluble Aβ can be removed from the brain via two basic mechanisms: favoring its transportation across the
Mechanisms of β-amyloid toxicity
Various mechanisms are proposed to explain the pathway by which Aβ induces neuronal cell death, including intracellular calcium accumulation, reactive oxygen species (ROS) and nitric oxide production, inflammatory processes, and increased sensitivity to apoptosis.
Minor pathophysiologic hypothesis: the τ-protein cascade
Neurofibrillary tangles consist of paired helical filaments found in the cytoplasm of neurons primarily in the hippocampus [252]. The formation of neurofibrillary tangles in AD is related directly to abnormal function of protein τ. τ is a microtubule-associated phosphoprotein that plays a critical role in supporting axonal transport and promotion of cell stability. The major polypeptides of paired helical filaments are microtubule-associated protein τ. The level of τ in AD neocortex is
Summary
In the past 2 decades, huge progress has been made in understanding the cellular and molecular processes that initiate and feed the AD cascade. The enhanced knowledge of the pathophysiology of AD lays the groundwork for significant improvements in the diagnosis and pharmacologic treatment of the disease. Fundamental advancement has been made in understanding the genetic basis of the disease with the identification of causative genes (APP, PS-1, and PS-2) for early-onset familial AD. In
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2021, Process BiochemistryCitation Excerpt :sAPPβ is smaller than sAPPα. CTF-99 is further processed by γ-secretase releasing an amyloid intracellular domain (ACID) and Aβ fragment [6–9]. Oceans cover more than 70 % of the earth’s surface along with diverse marine organisms that are rich sources of natural products [10,11].