Major Advances in Alzheimer's Disease – Restoring Cognitive Ability and the Role of Chronic Gum Disease

Alzheimer's disease (AD) continues to be a leading cause of dementia and ultimately death, with over 44 million estimated to be suffering from the disease worldwide, and only 1-in-4 receiving an official diagnosis. 

Drug therapies have proved largely unsuccessful. Last year, a promising BACE1 inhibitor – a class of drugs which prevent the formation of toxic amyloid-β plaques – was dropped due to safety concerns. Another was found to reduce levels of amyloid-β, but without any significant improvements in cognition. Another type of drug – an antibody which seeks out and breaks down amyloid-β – was able to reduce levels of amyloid-β, but only at the highest dose and with significant side effects. The search for effective drug treatments continues. 

The role of epigenetics – i.e. environmentally-dependent and heritable changes in DNA structure which regulate the expression of genes without altering the nucleotide sequence itself – is being increasingly recognised in the disease pathology of psychiatric, neurodegenerative and mood disorders across the board, including in Alzheimer's.

A paper [1] last week found significant elevations of the histone methyltransferases EHMT1/2, which catalyse repressive histone H3 methylation (linked to gene silencing) in the prefrontal cortex of mice representing a late-stage familial Alzheimer's disease (FAD) mouse model, ultimately leading to a decreased expression and function of glutamatergic AMPA and NMDA receptors in the prefrontal cortex. Such epigenetic changes have also been observed [2] in human post-mortem tissue of human AD patients and are thought to, at least in part, underlie the progressive cognitive decline seen in the later stages of the disease. When the mice were treated with an EHMT1/2 inhibitor (BIX-01294 or UNC0642 [3,4]) or virally-mediated EHMT1/2 gene knockdown, these changes were reversed and glutamate receptor expression and function was restored in the prefrontal cortex and hippocampus. Significantly, the cognitive impairments in object-recognition, working memory and spatial memory usually exhibited in late-stage FAD mice were consistently (albeit temporarily) restored to that of wild-type controls in a T-Maze delayed-alternation task, novel object recognition task and the Barnes maze, respectively – suggesting a potential new therapeutic target in the treatment of Alzheimer's disease, independent of the amyloid-β deposits and tauopathy thought to underlie the disease pathology. Future research will look at whether treatment with EHMT1/2 inhibitors could restore cognitive function and memory deficits in Alzheimer's patients.

Back to the amyloid-β hypothesis – which may be a contributing factor to the aforementioned epigenetic changes – a separate research paper [5] last week showed that the bacterium porphyromonas gingivalis (P. gingivalis) may play a central role in the pathogenesis of Alzheimer's disease.

Gingipains (red) bind to amyloid-β

S. Dominy et al., Science Advances 5, 2019.

The bacterium – commonly associated with chronic periodontitis (gum disease) – has previously been identified as a risk factor in the development of AD and has been directly correlated with a greater accumulation of amyloid-β plaques [6] in humans. In the current study the bacterium was identified in the cerebrospinal fluid of 10 suspected AD patients. P. gingivalis produces toxic proteases known as gingipains, which have been shown to drive the host colonisation and pathogenesis [7] of the bacterium. Oral infection with P. gingivalis in mice consistently increased production of Aβ1–42, a key component of the toxic amyloid plaques known to underlie neurotoxicity and neuroinflammation in AD. Furthermore, when the researchers injected gingipains into mice, the mice consistently developed the hallmark tau and ubiquitin pathology assosciated with AD, and showed significantly greater neurodegeneration than saline-injected mice. The researchers therefore administered selective, small-molecule gingipain inhibitors in vivo, and found that not only was the host Aβ1–42 response to P. gingivalis infection significantly decreased, but the associated neurodegeneration was successfully blocked. Future research will continue to investigate whether selective gingipain inhibitors able to cross the blood-brain-barrier may represent a potential new mode of treatment for Alzheimer's disease, as well as the link between P. gingivalis infection and apolipoprotein E4 (APOE4). An orally bioavailable, brain-penetrant gingipain inhibitor is already being tested in human clinical trials.

The research supports the recently emerging hypothesis that amyloid-β may act as an antimicrobial peptide [8,9], with mutations contributing to its dysfunction leading to a more robust response to infection with P. gingivalis (amongst other microbes) and thus an increased risk of neurotoxicity. The authors further propose that genetic polymorphisms of innate immune system genes may result in defective clearance of P. gingivalis and its associated gingipains from the brain, resulting in chronic, low-level infection and neuroinflammation in susceptible individuals. Neuroinflammation has long been known to be a significant causal factor in AD pathology.

Exciting advances – both a new target to reduce aberrant amyloid-β production and subseqeunt neurodegeneration in Alzheimer's before it occurs, and a novel target to potentially restore cognitive function in the later stages of the disease.


References:
[1] Zheng, Y., Liu, A., Wang, Z.-J., Cao, Q., Wang, W., Lin, L., Ma, K., Zhang, F., Wei, J., Matas, E., et al. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease. Brain. Available at: https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awy354/5298257 [Accessed January 28, 2019].

[2] Narayan, P., and Dragunow, M. (2017). Alzheimer’s Disease and Histone Code Alterations. In Neuroepigenomics in Aging and Disease Advances in Experimental Medicine and Biology., R. Delgado-Morales, ed. (Cham: Springer International Publishing), pp. 321–336. Available at: https://doi.org/10.1007/978-3-319-53889-1_17.

[3] Kubicek, S., O’Sullivan, R.J., August, E.M., Hickey, E.R., Zhang, Q., Teodoro, M.L., Rea, S., Mechtler, K., Kowalski, J.A., Homon, C.A., et al. (2007). Reversal of H3K9me2 by a Small-Molecule Inhibitor for the G9a Histone Methyltransferase. Molecular Cell 25, 473–481.

[4] Liu, F., Barsyte-Lovejoy, D., Li, F., Xiong, Y., Korboukh, V., Huang, X.-P., Allali-Hassani, A., Janzen, W.P., Roth, B.L., Frye, S.V., et al. (2013). Discovery of an in vivo Chemical Probe of the Lysine Methyltransferases G9a and GLP. J Med Chem 56. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880643/.

[5] Dominy, S.S., Lynch, C., Ermini, F., Benedyk, M., Marczyk, A., Konradi, A., Nguyen, M., Haditsch, U., Raha, D., Griffin, C., et al. (2019). Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances 5, eaau3333.

[6] Kamer, A.R., Pirraglia, E., Tsui, W., Rusinek, H., Vallabhajosula, S., Mosconi, L., Yi, L., McHugh, P., Craig, R.G., Svetcov, S., et al. (2015). Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiology of Aging 36, 627–633.

[7] Stathopoulou, P.G., Galicia, J.C., Benakanakere, M.R., Garcia, C.A., Potempa, J., and Kinane, D.F. (2009). Porphyromonas gingivalis induce apoptosis in human gingival epithelial cells through a gingipain-dependent mechanism. BMC Microbiol 9, 107.

[8] Soscia, S.J., Kirby, J.E., Washicosky, K.J., Tucker, S.M., Ingelsson, M., Hyman, B., Burton, M.A., Goldstein, L.E., Duong, S., Tanzi, R.E., et al. (2010). The Alzheimer’s Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide. PLOS ONE 5, e9505.

[9] Kumar, D.K.V., Choi, S.H., Washicosky, K.J., Eimer, W.A., Tucker, S., Ghofrani, J., Lefkowitz, A., McColl, G., Goldstein, L.E., Tanzi, R.E., et al. (2016). Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Science Translational Medicine 8, 340ra72-340ra72.