The Flipons, Infections, and Amyloids that Foreshadow the Fading Memories of Alzheimer's Disease

Abstract

Our memories are almost magical. We can experience an event for a short moment in time and quickly recall it decades later. This review explores the impact of some relatively new discoveries in the field of flipon biology that provide insight into diseases associated with impaired memory function. I examine how an ancient immune system based on Z-DNA and Z-RNA (collectively called ZNAs) regulates pathways that impact the memories modeled by synapses. The outcomes depend on intracellular defenses activated by endogenous retroelements (ERE) and virus, and on extracellular responses to ZNAs in bacterial biofilms. The bacterial amyloids and complement activation pathways further exacerbate the decline of cognitive and affective functions by inducing remodeling of synapses. In addition to immune EREs, a class of memory EREs potentially acts as ribotransmitters. These RNAs are transported across the synapse to program the connections between neurons that underlie the formation and remodeling of memories. Examples exist of ribotransmitters derived from ERE transcripts and assembled into capsids capable of transsynaptic transmission. In contrast, the immune EREs protect the nervous system by dismantling synapses to prevent viruses and retrotransposons from crossing them. The complexity of the interactions between memory and immune EREs likely give rise to the inverted U-shaped dose-response curves for the therapeutics currently available to treat cognitive decline. Other approaches for disease prevention are suggested, along with those that promote the regeneration and reprogramming of neuronal circuits.

Keywords: Alzheimer’s disease; Flipons; Z-DNA and Z-RNA; bacterial infection; complement; endogenous retroelements; viruses.

Figure 1.

Modeling memory. (a) Cantor sets illustrate how information can be stored and regenerated from a set of points (corresponding to synapses) using a symmetrical algorithm to generate and reconstruct memory. (b) Here, an asymmetrical algorithm generates barcodes at each layer corresponding to the input. Syncing the barcode with neighbors ensures robust performance, even when inputs are missing. In this example, the output regenerates features absent from the original input. Sharing of the barcode across senses enhances the correlation between the features detected by each.

Figure 2.

The complex pathways involved in the response to double-stranded RNAs produced by viruses and endogenous retroelements. In normal cells, dsRNA is sensed by the constitutive p110 isoform of ADAR with effects on splicing and editing of nuclear RNAs. In the cytoplasm, dsRNA is sensed by MDA5, inducing an interferon response that drives the expression of PKR, the p150 isoform of ADAR1, and ZBP1. Sensing of dsRNA by PKR leads to phosphorylation of EIF2α, inhibiting translation of capped mRNA and leading to the formation of stress granules. Cytoplasmic ADAR1 p150 is a negative regulator of these responses, binding and editing dsRNA, binding Z-RNAs, and forming complexes with helicases and proteins like PACT (Protein Activator of PKR, encoded by PRKRA) that oppose further activation of MDA5 and PKR. The binding of Z-RNAs formed in dsRNA regions and instress granules diminishes the activation of ZBP1. The proteins involved are further described in the text, and additional details are given in the following figures. ZBP1 is also activated by ZNAs released from damaged mitochondria. ZNAs also accumulate during nuclear DNA replication, especially when a cell is stressed or exposed to radiation or other mutagens.

Figure 3.

ADAR1 p150 and ZBP1 are the only two proteins in the human genome with a ZNA structure-specific Zα domain. Both proteins are induced by interferon. (a) ADAR1 p150 negatively regulates interferon responses by inducing the disassembly of MDA5 filaments, and by destabilizing dsRNAs through adenosine to inosine editing. (b) ADAR1 also squelches binding of ZBP1 to ZNAs. The interaction prevents the activation of ZBP1. ZBP1 induces a number of responses listed on the fight that protect the host from infections and cancers. These outcomes are detailed in Figure 6.

Figure 4.

Ribotransmitters and Memory formation. In this model, memory and immune ERE (endogenous retroelement) RNAs regulate translation of transcripts in boutons and spines by modulation of protein kinase RNA (PKR) activity. PKR otherwise switches the eukaryotic initiation factor usage from EIF2α to EIF4G2, leading to the preferential translation of stress-responsive mRNAs. Memory EREs enhance synaptic connectivity while immune ERE dismantle connections to prevent transmission of retrotransposons and viruses across the synapse. ADAR p150 binds Z-RNAs to negatively regulate interferon response by inhibiting MDA5 filament formation and editing immune ERE. PKR also mediates the phosphorylation of Tau, altering the release and uptake of synaptic vesicles. Downregulation of these processes would limit the spread of viruses. Encapsulating pathogens and viral factories in β-amyloid (Aβ) cages would disrupt their replication and enhance intracellular immunity.

Figure 5.

The structure of Aβ1-42 from Protein Database Entry 2NAO. (a) Here, the structures are positioned to emphasize the β-sheet stacks and their potential to assemble into extended arrays. (b) The positions of Aβ1-42 residues. (c) The potential contacts between dimers of Aβ1-42 are involved in forming arrays. The sequence below highlights the E22 and K28 residues involved in the contacts. (d) The location of the Aβ42 peptide in the Amyloid-beta-precursor protein. The wild-type sequence of the peptide is shown along with a set of sequence variants that affect the risk of familial Alzheimer’s Disease. The variants are located where the amyloid monomers contact each other. The position of E28 is highlighte in red and K28 in blue.

Figure 6.

ZNA-dependent phenotypes in stressed cells. (a) Different non-genetically templated scaffolds are used in normal cells, compared to (b) those scaffolds present in stressed cells, as described in the text. (c) The inverted U-shaped dose-response curve, where functional outcomes vary with a therapeutic’s overall mechanism of action. Interferon and complement limit infection at lower doses; they disrupt memory at higher levels. Loss of amyloid protects against plague formation but not against bacterial infection. At high levels, cellular stress is neurotoxic. The balance between protection and loss of neural function likely varies by brain region and by individual.