Volume 362:329-344     

Figure 1. Processing of Amyloid Precursor Protein. 

 

In Panel A, cleavage by α-secretase interior to the β-amyloid peptide (Aβ) sequence initiates nonamyloidogenic processing. A large amyloid precursor protein (sAPPα) ectodomain is released, leaving behind an 83-residue carboxy-terminal fragment. C83 is then digested by γ-secretase, liberating extracellular p3 and the amyloid intracellular domain (AICD). Amyloidogenic processing is initiated by β-secretase beta-site amyloid precursor protein–cleaving enzyme 1 (BACE-1), releasing a shortened sAPPα. The retained C99 is also a γ-secretase substrate, generating Aβ and AICD. γ-Secretase cleavage occurs within the cell membrane in a unique process termed “regulated intramembranous proteolysis.” sAPPα and sAPPβ are secreted APP fragments after α-secretase and β-secretase cleavages, respectively. AICD is a short tail (approximately 50 amino acids) that is released into the cytoplasm after progressive ε-to-γ cleavages by γ-secretase. AICD is targeted to the nucleus, signaling transcription activation. Lipid rafts are tightly packed membrane micro-environments enriched in sphingomylelin, cholesterol, and glycophosphatidylinositol (GPI)–anchored proteins. Soluble Aβ is prone to aggregation. 
 In Panel B, left inset, protofibrils (upper) and annular or porelike profiles (lower) are intermediate aggregates. (Photomicrographs courtesy of Hilal Lashuel, Ph.D.) In the right inset, self-association of 2 to 14 Aβ monomers into oligomers is dependent on concentration (left immunoblot). In the right immunoblot, oligomerization is promoted by oxidizing conditions (lane 2) and divalent metal conditions (lane 3). (Immunoblots courtesy of Hongwei Zhou, Ph.D.)


Figure 2. Tau Structure and Function.


Four repeat sequences (R1-R4) make up the microtubule-binding domain (MBD) of tau. Normal phosphorylation of tau occurs on serine (S; inset, above horizontal bar) and threonine (T; inset, below horizontal bar) residues, numbered according to their position in the full tau sequence. When followed by proline (P), these amino acids are phosphorylated by glycogen synthase kinase 3 (GSK-3β), cyclin-dependent kinase (cdk5) and its activator subunit p25, or mitogen-activated protein kinase (MAPK). Nonproline-directed kinases — Akt, Fyn, protein kinase A (PKA), calcium–calmodulin protein kinase 2 (CaMKII), and microtubule affinity-regulating kinase (MARK) — are also shown. KXGS (denoting lysine, an unknown or other amino acid, glycine, and serine) is a target motif. Hyperphosphorylated sites specific to paired helical filament tau in Alzheimer's disease tend to flank the MBD. Tau binding promotes microtubule assembly and stability. Excessive kinase, reduced phosphatase activities, or both cause hyperphosphorylated tau to detach and self-aggregate and microtubules to stabilize.


Figure 3. Synaptic Dysfunction in Alzheimer's Disease.


Synaptic loss correlates best with cognitive decline in Alzheimer's disease. A control synapse is shown at the top of the figure. At the bottom of the figure, an “Alzheimer's disease synapse” depicting the pleiotropic effects of the β-amyloid peptide (Aβ) is shown. Rings represent synaptic vesicles. Experimental application and expression of Aβ, especially oligomers, impair synaptic plasticity by altering the balance between long-term potentiation (LTP) and long-term depression (LTD) and reducing the numbers of dendritic spines. At high concentrations, oligomers may suppress basal synaptic transmission. Aβ facilitates endocytosis of receptors of N-methyl-D-aspartate (NMDAr) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPAr). Aβ also binds to the receptors of p75 neurotrophin (p75NTr) and brain-derived neurotrophic factor (the BDNF receptor, also known as the tyrosine kinase B receptor [trkBr]), exacerbating a situation in which levels of BDNF and nerve growth factor (NGF) are already suppressed. Aβ impairs nicotinic acetylcholine (ACh) receptor (nAChr) signaling and ACh release from the presynaptic terminal. Numbers of hippocampal synapses decrease in mild cognitive impairment in which remaining synaptic profiles show compensatory increases in size. 
APP denotes amyloid precursor protein, pCaMKII phosphorylated calcium–calmodulin–dependent protein kinase 2, pCREB phosphorylated cyclic AMP response-element-binding protein, trkAr tyrosine kinase A receptor, and VGCC voltage-gated calcium channel.


Figure 4. Oxidative Stress and Mitochondrial Failure.


A β-amyloid peptide (Aβ)–centric scheme depicts production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Their peroxidative attack on cell and organelle membrane lipids yields the mitochondrial toxins hydroxynonenal (HNE) and malondialdehyde. Oxidative damage to membrane-bound, ion-specific ATPases and stimulation of calcium (Ca2+) entry mechanisms — for example, glutamate (N-methyl-D-aspartate [NMDA]) receptors (NMDAr), membrane-attack complex (MAC) of complement, and ion-selective amyloid pore formation — cause cytosolic and mitochondrial Ca2+ overload. Cellular Aβ directly attacks electron transport complex IV (cytochrome c oxidase) and key Krebs-cycle enzymes (α-ketoglutarate and pyruvate dehydrogenase) and damages mitochondrial DNA (mtDNA), leading to fragmentation. Lipid peroxidation products also promote tau phosphorylation and aggregation, which in turn inhibit complex I. Exaggerated amounts of ROS and RNS are generated at complexes I and III. As the mitochondrial membrane potential (MPP) collapses and permeability-transition pores (ψm) open, caspases are activated.
 Aβ also induces the stress-activated protein kinases p38 and c-jun N-terminal kinase (JNK), as well as p53, which are further linked with apoptosis. Substrate deficiencies, notably NADH and glucose, combine with electron transport uncoupling to further diminish ATP production. Alcohol dehydrogenase was recently identified as the mitochondrial-binding target for Aβ. Endoplasmic reticulum contributions are shown. GLUT1, 4 denotes glucose transporter 1, 4.


Figure 5. Inflammation and Mechanisms of Aβ Clearance.


β-amyloid peptide (Aβ) is formed within intracellular compartments (the endoplasmic reticulum, Golgi apparatus, and endosomes) or it can enter multiple cell types through the low-density lipoprotein receptor–related protein. The ubiquitous apolipoprotein E (APOE) and α2- macroglobulins (α2M) are chaperones in this process and in the genesis of extracellular plaques. Microglia directly engulf Aβ through phagocytosis. Astrocytes also participate in Aβ clearance through receptor-mediated internalization and facilitation of its transfer out of the central nervous system and into the circulation. Microglia and astrocytes are recruited and stimulated in Alzheimer's disease to release proinflammatory cytokines and acute-phase reactants. Receptors for advanced glycation end products (RAGE) molecules transduce extracellular Aβ toxic and inflammatory effects and mediate influx of vascular Aβ. The inflammatory milieu provokes neuritic changes and breakdown of the vascular blood–brain barrier. In addition to cell-mediated reactions, Aβ clearance occurs through enzymatic proteolysis, mainly through neprilysin (Nep) and insulin-degrading enzyme (IDE).
 Aβ oligomers block proteasome function, facilitating the buildup of intracellular tau and accumulation of Aβ into "aggresomes." APP denotes amyloid precursor protein, MMP matrix metalloproteinase, MOTC microtubule-organizing center, and MVB multivesicular body.

 

 

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