Abstract
Alzheimer’s disease (AD) is defined by memory loss and cognitive impairment, along with the accumulation in brain of two types of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Both plaques and tangles are composed predominantly of poorly soluble filaments that respectively assemble from amyloid-β (Aβ) peptides and the neuron-specific, microtubule-associated protein, tau. It is now widely acknowledged that soluble oligomers of Aβ and tau, the building blocks of plaques and tangles, are principal drivers of AD pathogenesis by acting coordinately to impair and destroy synapses, and kill neurons. The behavioral features of AD are a direct consequence of these attacks on synapses and neuronal viability, which in turn reflect a reduced capacity of AD neurons to utilize energy sources needed to maintain neuronal function and vitality. In other words, AD neurons are starving, even when they may be surrounded by abundant nutrients. Here, we review some of the evidence for the metabolic deficiencies of neurons in AD and how they impact neuronal health.
Highlights
The well known behavioral symptoms of Alzheimer’s disease (AD) are caused by two phenomena: the compromised function and eventual loss of synapses on neurons that mediate memory and cognition, and by the death of those neurons.A detailed understanding of the molecular mechanisms that cause neuronal decline in AD has been frustratingly slow to develop
Whereas the filaments in plaques are made from amyloid-b (Ab) peptides, which are derived by proteolysis from the widely expressed, single pass transmembrane protein, APP (Kang et al, 1987; Masters et al, 1985), the filaments in tangles assemble from the neuronspecific protein, tau (Grundke-Iqbal et al, 1986; Kondo et al, 1988; Kosik et al, 1988), which is normally found primarily in association with axonal microtubules (Binder et al, 1985; Weingarten et al, 1975)
We recently reported that Ab oligomers (AbOs) and tau work together to cause dysregulation of normal mTORC1 signaling as a requisite step for neuronal cycle re-entry (CCR) (Norambuena et al, 2017)
Summary
The well known behavioral symptoms of Alzheimer’s disease (AD) are caused by two phenomena: the compromised function and eventual loss of synapses on neurons that mediate memory and cognition, and by the death of those neurons. A detailed understanding of the molecular mechanisms that cause neuronal decline in AD has been frustratingly slow to develop Gaining such an understanding, is bound to enhance efforts to devise effective means of preventing AD onset or significantly slowing its progression. The past 15 years, have witnessed a growing realization that the cellular and molecular processes leading to neuronal decline in AD begin decades before symptoms are evident (Villemagne et al, 2013), and that those processes are driven by soluble, misfolded forms of Ab and tau independently of their respective incorporation into plaques and tangles (Bloom, 2014). Emerging from that body of work and related approaches is the realization that AD neurons are chronically undernourished because they cannot effectively use abundant nutrients and trophic factors that surround them
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