Emerging concepts of how β-amyloid proteins and pro-inflammatory cytokines might collaborate to produce an 'Alzheimer brain' (Review)

Three steps lead to the development of full-blown sporadic or late-onset Alzheimer's disease or dementia (AD). In the young brain, amyloid beta-(1-42) (A beta 42) is a normal aggregation-prone protein product of neuronal activity that is kept at a safe low level by proteolysis in neurons and glial cells, and by expulsion across the blood-brain barrier. But clearance declines with advancing age. Step 1: Because of the normal decline with age of the A beta 42-clearing mechanisms, toxic amyloid-derived diffusible ligands (ADDLs) made of dodecamers of the aggregation-prone A beta 42 start accumulating. These A beta 42 dodecamers selectively target the initially huge numbers of excitatory synapses of neurons and cause them to start slowly dropping, which increasingly impairs plasticity and sooner or later starts noticeably affecting memory formation. At a certain point, this increasing loss of synapses induces the neurons to redirect their still-expressed cell cycle proteins from post-mitotic jobs, such as maintaining synapses, to starting a cell cycle and partially or completely replicating DNA without entering mitosis. The resulting aneuploid or tetraploid neurons survive for as long as 6-12 months as quasi-functional 'undead zombies', with developing tangles of hyperphosphorylated T protein disrupting the vital anterograde axonal transport of mitochondria and other synapse-vital components. Step 2: The hallmark AD plaques appear as A beta 42 clearance continues to decline and the formation of A beta 42 non-diffusible fibrils be-ins in the aging brain. Step 3: A terminal cytokine-driven maelstrom begins in the aging brain when micro-glia, the brain's professional macrophages, are activated in and around the plaques. They produce pro-inflammatory cytokines, such as IFN-gamma, IL-1 beta and TNF-alpha. One of these, IFN-gamma, causes the astrocytes enwrapping the neuronal synapses to express their beta-secretase (BACE1) genes and produce and release A beta 42, which can kill the closely apposed neurons by binding to their p75(NTR) receptors, which generate apoptogenic signals. Astrocytes are also stimulated by the same cytokines to turn oil their nitric oxide synthase (NOS)-2 genes and start pouring large amounts of nitric oxide (NO) and its cytocidal derivative peroxynitrite (ONOO-) directly Out onto the closely apposed neurons.