Alzheimer Disease Pathogenesis: Insights From Molecular and Cellular Biology Studies of Oligomeric Aβ and Tau Species

Abstract

Alzheimer disease (AD) represents an oncoming epidemic that without an effective treatment promises to exact extraordinary human and financial burdens. Studies of pathogenesis are essential for defining targets for discovering disease-modifying treatments. Past studies of AD neuropathology provided valuable, albeit limited, insights. Nevertheless, building on these findings, recent studies have provided an increasingly rich harvest of genetic, molecular and cellular data that are creating unprecedented opportunities to both understand and treat AD. Among the most significant are those documenting the presence within the AD brain of toxic oligomeric species of Aβ and tau. Existing data support the view that such species can propagate and spread within neural circuits. To place these findings in context we first review the genetics and neuropathology of AD, including AD in Down syndrome (AD-DS). We detail studies that support the existence of toxic oligomeric species while noting the significant unanswered questions concerning their precise structures, the means by which they spread and undergo amplification and how they induce neuronal dysfunction and degeneration. We conclude by offering a speculative synthesis for how oligomers of Aβ and tau initiate and drive pathogenesis. While 100 years after Alzheimer's first report there is much still to learn about pathogenesis and the discovery of disease-modifying treatments, the application of new concepts and sophisticated new tools are poised to deliver important advances for combatting AD.

Keywords: Alzheimer disease; Aβ; Down syndrome; PET; amyloid plaques; neurofibrillary tangles; oligomer; tau.

FIGURE 1

The diagram of APP processing. The type 1 transmembrane protein APP is processed by two pathways: the nonamyloidogenic pathway and the amyloidogenic pathway. In the nonamyloidogenic pathway, APP is cleaved by α-secretase to produce the soluble sAPPα and the C-terminal fragments, α-CTF (C83), which is then cleaved by γ-secretase to yield the APP intracellular domain (AICD) and P3 peptide; while in the amyloidogenic pathway, β-secretase cleaves APP to produce the soluble fragment sAPPβ and the C-terminal fragments, β-CTF (C99). C99 is then cleaved by γ-secretase to release AICD and Aβ peptides of varying length.

FIGURE 2

Speculative scheme to explain AD pathogenesis. Overview of pathogenesis is summarized in the red boxed caption at the bottom. Initiating pathogenesis: The process would be initiated by the formation of AβOs in cortical neurons. The source of AβOs would include those produced locally within the presynaptic terminals of cortical neurons innervating entorhinal cortex. AβOs produced in the somatodendritic domain of cortical neurons could serve as the nidus for local amyloid plaque deposition and would be in contact with axons of entorhinal cortical neurons. Thus, AβOs produced in both the cortico-entorhinal and entorhinal-cortical projections may participate in formation of AβOs, The initial focus of AβO actions (signified by boxed number 1) may be registered in superficial entorhinal cortex whose neurons receive cortical inputs. At later stages retrograde AβOs acting on entorhinal axons in cortex may contribute to pathogenesis, as may AβOs produced in entorhinal afferents to cortex (boxed 3). Driving pathogenesis: AβO acting on entorhinal neurons would catalyze formation of tau oligomers with subsequent spread and propagation in connected neurons, first in hippocampus and subiculum and then association neocortex (boxed 2). Toxic tau oligomers could exert injury to the neurons in which they are formed and following release to the synapses and neurons to which they spread and in which they propagate (boxed 3). AβOs could interact during this phase with tau oligomers to enhance synaptic and neuronal dysfunction. Neurons in the locus coeruleus, basal forebrain cholinergic complex and raphe nuclei may owe their selective vulnerability to their connections with both neocortex and hippocampus during early and later phases (boxed 1, 2, 3). Curved red arrows signify local production of AOs due to processing of APP. Green solid line (near boxed 1) indicates the anterograde transport of APP for processing at the presynapse during the initial phase; AβOs produced in somatodendritic domains could also be transported anterogradely at this stage (green line). Brown dashed line represents the direction of tau oligomer spread. LC, locus coeruleus neuron; BFCN, basal forebrain cholinergic neuron; and EC, entorhinal cortex neuron.