Subcellular injuries in Alzheimers disease: illustration o

FIGURE LEGEND: Schematic illustration of the subcellular injuries observed during each of the four general stages of Alzheimer's disease in hippocampal neurons and perineural cells. Each frame (A-D) features the organelles of the same neuron, and that neuron\u2019s interactions with the processes of two other neurons: the postsynaptic density and spine of a dendrite (far right), and an afferent axon at the top center. Elements that represent subcellular injuries during the progression of AD are highlighted by red coloring (dark in grayscale printing), and they change from stage to stage. Labels of cell types and normal subcellular features are given only in frame A. (A) First stage, before accumulation of A\u03b2, showing proliferation of endosomes and lysosomes, decreased Golgi quality control (QC), normal synaptic function, and normal microtubule transport of vesicles and mitochondria. (B) Second stage, before structural changes are observed, showing increased permeability and cholesterol content of the plasma membrane, increased influx of calcium ions at the presynaptic terminal, the consequent excessive release of neurotransmitter vesicles, and excitotoxicity to the post-synaptic neuron. (C) Third stage, intracellular inflammatory processes, showing atrophy of the astrocyte cell and various injuries to the neuron\u2019s nucleus, ER, Golgi, and mitochondrion, which include protein accumulation and defects, increased cholesterol, and decreased steroids and ATP. The synaptic terminal is now shown depleted of vesicles and the post-synaptic spine suffers loss of receptors, decreased LTP, and altered structure. (D) Fourth stage, neuroinflammatory response and cell death, showing an activated, macrophagic microglial cell producing a toxic neuroinflammatory response, including secretion of IL-1. The IL-1 contributes to hyperphosphorylation of tau proteins on the microtubules, causing their degeneration. The axon is shown degenerating due to the loss of transport from the degenerating microtubules. The astrocyte cell is now hypertrophied, and its reduction in peri-synaptic uptake of glutamate neurotransmitter is shown to cause further excitotoxic effects and axonal degeneration at the afferent synapse at the top. Autophagic processes are shown, leading to apoptosis. Amyloid plaques from the continual accumulation of A\u03b2 are shown fully developed.