Beyond Amyloid and Tau - Targeting Lipid Metabolism for Alzheimer’s Disease Biomarkers and Therapies

Dear Colleagues,

Alzheimer’s disease (AD) was described over a century ago by Dr. Alois Alzheimer as a “peculiar disease of the cerebral cortex” characterized by plaques and tangles. Plaques are composed of neurotoxic amyloid peptides containing 42 amino acids but are recognized to be disjunct from cognitive and memory deficits that are the major clinical features of AD. Tangles, characterized by hyperphosphorylated tau protein, closely mirror AD pathology, but interventions targeting tau may be too late since memory is already compromised when hyperphosphorylated tau is detectable. The disturbing failures of blockbuster drugs targeting amyloid biology to halt these clinical decline has resulted in a call for the examination of alternative pathways that may closely impact the progression of AD. To this effect, this Special Issue will propose several pre-symptomatic mechanism-based pathways that are not exclusive but can be combined with amyloid or tau to better understand AD pathology. These pathways are based on lipid metabolism and define several key aspects of neuronal function. Mechanistically, there are interactions of several of these lipid pathways with all known factors hypothesized to play a role in AD. Amyloid peptides are derived from the lipid membrane-bound amyloid precursor protein (APP), and the processing of APP is influenced by the lipid environment. The modification of APP by fatty acids also influences its processing. Moreover, inflammatory pathways associated with AD pathology are known to involve lipid mediators of inflammation. Receptor-mediated pathways linked with AD pathology are influenced by lipids through intracellular signaling or through exocytosis or endocytosis at synaptic junctions. The auto-phagocytic process that clears toxic amyloid is regulated by lipids and Genome-wide association studies have identified several AD-associated genetic variants with lipid metabolic pathways as a common factor. Finally, lipids that are a major source of energy and thus contribute to mitochondrial function and energy balance are linked to AD pathology. The aforementioned interplay of lipid metabolism with AD pathology suggests that lipid pathways may represent alternative indicators and therapeutic targets for AD. Thus, the lipid metabolic space provide distinct as well as intersecting mechanisms with the well-studied amyloid pathology. The major lipid processes involve dietary uptake, processing by organs (liver, intestines, and muscle) or the microbiota, transport to the brain, metabolism for energy production or for generating lipid mediators that enhance or resolve inflammation. In this Special Issue, we will examine lipid uptake, transport, and metabolism in AD and pinpoint several potential aspects of control that can mitigate AD progression. The resulting set of articles will be of interest to researchers in the industry and academia who aim to explore AD pathology beyond amyloid and look at novel drug targets and biomarkers of AD, since lipid pathways provide mechanisms and useful checkpoints for rational interventions.

Dr. Alfred N. Fonteh
Guest Editor

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