Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis

Abstract

The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. Amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop. Because soluble toxic aggregates of both Aβ and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate.

Figure.. Signaling From Amyloid-β (Aβ) Through Tau Drives Alzheimer Disease (AD) Progression

Pathological Aβ species accumulate in the brain because of simple genetic insults, such as the rare amyloid precursor protein (APP) and presenilin mutations that cause familial early-onset AD, and the presence of apolipoprotein E4 (ApoE4), the protein product of the ε4 allele of the APOE gene, which is the strongest genetic risk factor for late-onset AD. Complex genetic interactions and environmental risks, indicated here as other factors, also contribute to the accumulation of toxic Aβ species in late-onset AD. Toxic Aβ species stimulate formation of pathological tau by modulating protein kinases and phosphatases that regulate tau phosphorylation and by inducing tau misfolding. Toxic forms of tau mediate the synaptic dysfunction and neuron death that underlie memory and cognitive impairment in AD, so the signature adverse effects of Aβ require tau.