Affiliations: [a] Department of Neuroscience, University of Florida, Gainesville, FL, USA
| [b] Anatomical Institute, University of Leipzig, Leipzig, Germany
Correspondence:
[*]
Correspondence to: Wolfgang J. Streit, PhD, Department of Neuroscience, 1149 S. Newell Drive, University of Florida College of Medicine, Gainesville, FL 32611, USA. E-mails: pschorr@ufl.edu or streit@mbi.ufl.edu; ORCID: 0000-0003-4973-9052.
Abstract: Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.
