Molecular Pathogenesis of Alzheimer's Disease: An Update

Abstract

Dementia is a chronic or progressive syndrome, characterized by impaired cognitive capacity beyond what could be considered a consequence of normal aging. It affects the memory, thinking process, orientation, comprehension, calculation, learning ability, language, and judgment; although awareness is usually unaffected. Alzheimer's disease (AD) is the most common form of dementia; symptoms include memory loss, difficulty solving problems, disorientation in time and space, among others. The disease was first described in 1906 at a conference in Tubingen, Germany by Alois Alzheimer. One hundred and ten years since its first documentation, many aspects of the pathophysiology of AD have been discovered and understood, however gaps of knowledge continue to exist. This literature review summarizes the main underlying neurobiological mechanisms in AD, including the theory with emphasis on amyloid peptide, cholinergic hypothesis, glutamatergic neurotransmission, the role of tau protein, and the involvement of oxidative stress and calcium.

Keywords: Alzheimer's disease; Amyloid; Dementia; Neurobiology; Pathogenesis; Review.

Fig. 1

Amyloidogenic and non-amyloidogenic processing of the APP. The top part of the figure shows the 2 main paths in the processing of APP, the most important elements involved, and the main alterations associated with the amyloidogenic pathway of APP. The bottom part of the figure shows potential modulators of the secretase activity (activation of receptors, growth factors, cytokines, hormones). α, α-secretase activity; β, β-secretase activity; γ, γ-secretase activity; BACE1, β-site – APP – cleaving enzyme 1; βA, amyloid β peptide; ADAM, α-secretase; APPsα and APPsβ, soluble portions produced by the effect of α- and β-secretase; C83, fragment of 83 amino acids of the carboxyl terminal portion produced by the effect of α-secretase; C99, fragment of 99 amino acids of the carboxyl terminal portion produced by effect of β-secretase; p3, peptide resulting from γ-secretase; AICD, carboxy-terminal fragment referred to as the intracellular domain of APP; T, Tau protein; mAChRs, muscarinic acetylcholine receptors; mGluR, metabotropic glutamate receptors; 5HT, serotonin receptors; CRHR1, receptor 1 of the corticotropin-releasing hormone; PAC1R, receptor 1 of pituitary adenylate cyclase; FGF, EGF, NGF, growth factors of fibroblasts, epidermis and the nervous system respectively; DOR, opioid receptor δ; A2AR, adenosine receptor 2A; β2-AR, β2 adrenergic receptor; GPR3, receptor 3 coupled to protein G; CXCR2, chemokine receptor 2.

Fig. 2

Production of amyloid β peptide from sequential proteolytic breaks of the APP. The figure shows the sequence of phases in the processing of APP in the formation of amyloid β peptide and its oligomerization. Numbers (1, 2a, 2b, 3, 4, and 5) refer to intervention sites where the production of amyloid β peptide could be modulated with possible therapeutic utility. α, α-secretase cut site; γ, γ-secretase cut site γ; ε, cut site ε of γ-secretase; BACE, β-secretase; Aβ, amyloid β peptide; AICD, carboxy-terminal fragment referred to as APP intracellular domain.