Pathophysiology of Alzheimer's Disease

Neuropathology for the Neuroradiologist: Plaques and Tangles

“…The most abundant species of A␤ found in plaques are either 40 or 42 amino acid residues in length (Fig 1). 18,21,23,24 The ␤ designation is derived from the secondary structure of the constituent protein in which parallel strands of amino acids are laterally associated with each other due to hydrogen bondings to form a sheetlike configuration of protein known as a ␤-pleated sheet. Curiously, the name "amyloid" (derived from Latin "amylum" or starch), as coined by the famous German pathologist and statesman, Rudolph Ludwig Karl Virchow (1821-1902), is a misnomer, because he thought the protein was actually a starchlike compound, due to its behavior with periodic-acid-Schiff stain.…”

“…In Alzheimer's second patient, no NFTs were noted, leading some investigators to consider that A␤ pathology may precede and even promote pathologies. 23,48 To date, however, no proved mechanisms directly link the formation of NFTs to A␤ pathology. 37,49 Despite lingering uncertainties, most investigators would agree that the A␤ peptide plays a significant role in the pathogenesis of AD.…”

“…The A␤ peptide is derived from the metabolism of amyloid precursor protein (APP), a transmembrane glycoprotein processed through endoplasmic reticulum and endosomal and lysosomal pathways and possesses extracellular and intracellular components (Fig 2). 23 The prevalence of at least 10 identified isoforms of APP throughout the body suggests a potential role in normal cellular physiology. 23,34,45,50 Metabolism of APP can be accomplished through an ␣-secretase pathway or an alternate and competing ␤-␥-secretase pathway.…”

“…7,17 These tangles resemble condensed serpentine fibrils and are primarily composed of protein arranged in hyperphosphorylated paired helical strands (Fig 1). 23,34,41 Normal protein promotes the assembly of microtubules, which, in turn, help organize the 3D architecture of the neuron and assist in the transportation of protein and enzyme-containing vesicles essential in cell maintenance and function. 42 For unclear reasons, protein aggregates inside neurons and their processes, and microtubules tend to depolymerize.…”

“…In addition, aggregated protein itself may lead to neuronal dysfunction. 23,43 The cause for the abnormal phosphorylation is unclear, but altered function of several protein kinases or phosphatases or a maladaptation due to cellular or microenvironmental stress may be implicated. 44,45 Initially, the protein is dispersed within the neurons.…”