Related Experiment Videos
The relationship between the morphological subtypes of microglia and Alzheimer's disease neuropathology
Patrick Jarmo Paasila1, Danielle Suzanne Davies2, Jillian June Kril1
1Discipline of Pathology, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
Abstract:
Microglial associations with both the major Alzheimer's disease (AD) pathognomonic entities, β-amyloid-positive plaques and tau-positive neurofibrillary tangles, have been noted in previous investigations of both human tissue and mouse models. However, the precise nature of their role in the pathogenesis of AD is debated; the major working hypothesis is that pro-inflammatory activities of activated microglia contribute to disease progression. In contrast, others have proposed that microglial dystrophy with a loss of physiological and neuroprotective activities promotes neurodegeneration. This immunohistochemical study sought to gain clarity in this area by quantifying the morphological subtypes of microglia in the mildly-affected primary visual cortex (PVC), the moderately affected superior frontal cortex (SFC) and the severely affected inferior temporal cortex (ITC) of 8 AD cases and 15 age and gender-matched, non-demented controls with ranging AD-type pathology. AD cases had increased β-amyloid and tau levels compared to controls in all regions. Neuronal loss was observed in the SFC and ITC, and was associated with atrophy in the latter. A major feature of the ITC in AD was a decrease in ramified (healthy) microglia with image analysis confirming reductions in arborized area and skeletal complexity. Activated microglia were not associated with AD but were increased in non-demented controls with greater AD-type pathology. Microglial clusters were occasionally associated with β-amyloid- and tau-positive plaques but represented less than 2% of the total microglial population. Dystrophic microglia were not associated with AD, but were inversely correlated with brain pH suggesting that agonal events were responsible for this morphological subtype. Overall these novel findings suggest that there is an early microglial reaction to AD-type pathology but a loss of healthy microglia is the prominent feature in severely affected regions of the AD brain.
Insights
Alzheimer's disease (AD) involves brain changes like amyloid plaques and tau tangles. This study found that in severe AD, healthy microglia decrease, suggesting a loss of protective functions contributes to neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia interact with Alzheimer's disease (AD) hallmarks: beta-amyloid plaques and tau tangles.
- The role of microglia in AD pathogenesis is debated, with hypotheses including pro-inflammatory activation or loss of neuroprotective functions.
- Microglial morphological subtypes and their association with AD pathology require further clarification.
Purpose of the Study:
- To investigate microglial morphological subtypes in different brain regions affected by Alzheimer's disease.
- To correlate microglial morphology with AD neuropathology, neuronal loss, and brain pH.
- To elucidate the specific role of microglia in Alzheimer's disease progression.
Main Methods:
- Immunohistochemical analysis of microglial morphology in the primary visual cortex, superior frontal cortex, and inferior temporal cortex from AD cases and controls.
- Quantification of microglial morphological subtypes, including ramified (healthy) and activated microglia.
- Image analysis to assess microglial arborized area and skeletal complexity; correlation with AD pathology, neuronal loss, and brain pH.
Main Results:
- Alzheimer's disease cases showed increased beta-amyloid and tau levels across all regions.
- A significant decrease in ramified (healthy) microglia was observed in severely affected regions of the AD brain (Inferior Temporal Cortex).
- Activated microglia were not increased in AD but were found in non-demented controls with higher AD pathology; microglial clusters were rare.
Conclusions:
- Alzheimer's disease is characterized by an early microglial response to pathology.
- A prominent feature in severely affected AD brain regions is the loss of healthy, ramified microglia.
- This loss of healthy microglia, rather than activation, may be a key factor promoting neurodegeneration in advanced Alzheimer's disease.