Fig 1.
AD: Clinical symptomatology, forms, and Aβ and tau protein pathologies.
(A) AD clinical symptomatology. The “down” arrows represent impairment or disruption of the brain functions in AD patients while “up” arrows symbolize the increase. (B) Two AD forms, familial and sporadic, differing in time of the onset, progression rate, and a cause, can be recognized. The familial form is associated with autosomal dominant mutations leading to inherently increased production of Aβ, especially the highly fibrillogenic Aβ ending at residue 42, (Aβ1–42). By contrast, the sporadic form does not follow mendelian inheritance and its causative triggers remain unknown. The strongest known genetic factor is APOE4. (C) In AD, the monomers of Aβ, which are cleavage fragments of APP, aggregate into oligomers. The oligomers, especially the cytoplasmic ones, are believed to be the most toxic, although extracellular amyloid plaques are the most conspicuous outcome of the process. (D) The tau protein normally binds to and stabilizes microtubules within neuronal axons. In an AD patient brain, tau protein is hyperphosphorylated and accumulates into neurofibrillary tangles, which leads to destabilization of cytoskeleton, disruption of synapses, and finally death of neurons. Aβ, amyloid beta; AD, Alzheimer’s disease; APOE4, apolipoprotein E4 allele; APP, amyloid precursor protein; BACE1, beta-site APP-cleaving enzyme.
Fig 2.
Pathogens possibly associated with AD pathology and suggested ways of their entry into the brain.
On the left, the most important pathogens associated with AD discussed in this review. Pathogens inhabiting nasal and oral cavity can migrate through disrupted mucosa and then along the olfactory nerve (e.g., Chlamydia pneumoniae; left green arrow) or the trigeminal nerve (e.g., periodontal Treponema species and Herpes simplex virus type 1; middle yellow arrow). Microbes from both oronasal area and the periphery can enter the bloodstream during transient bacteremias or candidemias (e.g., Porphyromonas gingivalis, Candida albicans) and then attack the brain through disrupted BBB (right red arrow). Parasites like Toxocara canis also enter the CNS from the blood vessels. AD, Alzheimer’s disease; BBB, blood–brain barrier; CNS, central nervous system.
Fig 3.
Somatic APP gene recombination.
In human neurons, additional copies of the APP gene are created by the process of somatic recombination. The original APP gene (1) is undergoing standard transcription and splicing. Mature APP mRNAs (2) can undergo the process of reverse transcription (3) to complementary DNAs (cDNAs; 4), which can be retro-inserted into genomic DNA as genome-inserted complementary DNAs (gencDNAs; 5). The resulting additional copies of APP gene lack introns and often bear point mutations or exon deletions as both regular and reverse transcription are error prone, but can still be transcribed and translated (6). Moreover, the resulting mRNAs may undergo repeated cycles of retro-insertion, leading to accumulation of errors. We propose that cerebral infection provides some of the necessary ingredients for this mechanism, namely activation of APP expression (7), oxidative damage leading to DNA breaks (8), and a source of reverse transcriptase (9). Enhanced APP production by gene multiplication, and even the production of aggregation-prone mutant forms of amyloid beta (10) might act as an antimicrobial defensive mechanism (11). However, it is also harmful to the tissue itself, and as the mutant gencDNA insertion is irreversible, it may easily open the door to progressive neurodegeneration. APP, amyloid precursor protein; gencDNA, genome-inserted complementary DNA.
Fig 4.
Schematic illustrating the infectious hypothesis of AD.
The scheme follows the 3 main domains of AD: neuroinflammation, amyloid pathology, and tau protein pathology, progressing from the top to the bottom. Pathogens (bacteria, viruses, and/or fungi) entering the CNS activate the innate immunity. If the inflammatory process becomes chronic, the BBB is disrupted, facilitating entrance of further pathogens into the brain. Expression of APP and its cleavage to Aβ is enhanced in reaction to pathogens. Aβ monomers cluster into oligomers that can entrap various pathogens (agglutination or granuloma formation), which prevents them from entering into neurons, spreading or replicating, and facilitates their destruction by microglia. Aβ fibrils can directly disrupt pathogens’ membranes; however, they may attack neuronal membranes as well. During chronic or latent infections, Aβ fragments and fibrils accumulate, and finally create insoluble amyloid plaques. Tau pathology is stimulated by Aβ and neuroinflammation by several pathways and might be directly triggered by intracellular pathogens. An interesting question is whether tau protein could also serve as an intracellular antimicrobial peptide, similarly to Aβ oligomers. Accumulation of Aβ and tau is aggravated by impaired clearance activity of the brain glymphatic system, which is also compromised by neuroinflammatory processes. APOE4, the strongest known genetic risk factor of sporadic AD, apparently affects oligomerization or clearance of Aβ and facilitates entry of some pathogens (e.g., HSV1) into the cell. Aβ, amyloid beta; AD, Alzheimer’s disease; APOE4, apolipoprotein E4 allele; APP, amyloid precursor protein; BBB, blood–brain barrier; CNS, central nervous system; HSV1, Herpes simplex virus type 1; IL-6, interleukin-6; TNF, tumor necrosis factor.