The Catastrophe of Intracerebral Hemorrhage Drives the Capillary-Hemorrhage Dementias, Including Alzheimer’s Disease

Article type: Review Article

Authors: Stone, Jonathan^{a; *} | Mitrofanis, John^{b; c} | Johnstone, Daniel M.^{d; e} | Robinson, Stephen R.^{f; g}

Affiliations: [a] Faculty of Medicine and Health, University of Sydney, Sydney, Australia | [b] Université Grenoble Alpes, Fonds de Dotation, Clinatec, Grenoble, France | [c] Institute of Ophthalmology, University College London, London, UK | [d] School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia | [e] School of Medical Sciences, The University of Sydney, Sydney, Australia | [f] School of Health and Biomedical Sciences, RMIT University, Bundoora, Australia | [g] Institute for Breathing and Sleep, Austin Health, Heidelberg, Australia

Correspondence: [*] Correspondence to: Jonathan Stone, DSc, FAA, Professor Emeritus, University of Sydney, Sydney, Australia. Email: [email protected].

Abstract: This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer’s disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.

Keywords: Acquired resilience, Alzheimer’s disease, brain protection, capillary hemorrhage, dementia, glutamate excitotoxicity, hypoxia, immune-mediated cytotoxicity, neurotoxicity of hemoglobin, vascular aging

DOI: 10.3233/JAD-231202

Journal: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1069-1081, 2024