The relationship between the morphological subtypes of microglia and Alzheimer’s disease neuropathology

Paasila, Patrick Jarmo; Davies, Danielle; Kril, Jillian J.; Goldsbury, Claire; Sutherland, Greg T.

doi:10.1111/bpa.12717

Cited by 87 publications

(93 citation statements)

References 66 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, microglial dystrophy increases as NFD increases, and both of these degenerative processes are driven by aging (Figures and ). Subsequently, findings from other laboratories have reported reductions in microglial process lengths and arborizations occurring with aging and in AD (Davies, Ma, Jegathees, & Goldsbury, ), and most recently a loss of healthy microglia (Paasila, Davies, Kril, Goldsbury, & Sutherland, ). These results dovetail with earlier studies showing widespread microglial apoptosis in AD brain (Jellinger & Stadelmann, ; Lassmann, Schmied, Vass, & Hickey, ; Sugaya, Reeves, & McKinney, ; Yang et al, ).…”

Section: Microglial Dystrophy Is Unique To Human Aging and Linked To Nfdmentioning

confidence: 95%

Dystrophic microglia in late‐onset Alzheimer's disease

Streit

Khoshbouei

Bechmann

2020

Glia

115

View full text Add to dashboard Cite

Here, we summarize current understanding of functional involvement of microglial cells in the most common neurodegenerative disease to affect humans, which is sporadic or late‐onset Alzheimer's disease (LOAD). Our review narrowly focuses on insights obtained from post‐mortem neuropathological examinations of human brains paying particular attention to microglia as these cells have long been implicated as pivotal players in the cellular processes that lead to AD‐type neurodegeneration. Although complete understanding of the roles played by microglia in AD neurodegeneration remains elusive, our studies thus far have illuminated microglial involvement in LOAD, showing that microglial dystrophy, the morphological manifestation of senescence, can be integrated with other hallmark pathological features of AD, such as intraneuronal neurofibrillary degeneration (NFD) and extracellular deposits of amyloid‐beta (Aβ) protein. We have demonstrated an in situ correlation between microglial dystrophy and presence of NFD suggesting that neurodegeneration is secondary to aging‐related microglial deterioration, a concept founded on the notion that proper neuronal function is dependent on presence of healthy microglia. Diseased or weakened glia are detrimental for neuronal well‐being because their ability to provide neuronal support may be impaired. Our most recent work also links microglial dystrophy with Aβ deposits by showing that there is a chronic, yet futile microglial reaction to insoluble amyloid deposits. This inability of microglia to remove aggregated amyloid (a foreign body) causes microglial exhaustion and thereby exacerbates already ongoing aging‐dependent microglial deterioration. An eventual total loss of functional microglia in advanced LOAD promotes widespread NFD, dementia, and brain failure.

show abstract

Section: Microglial Dystrophy Is Unique To Human Aging and Linked To Nfdmentioning

confidence: 95%

Dystrophic microglia in late‐onset Alzheimer's disease

Streit

Khoshbouei

Bechmann

2020

Glia

115

View full text Add to dashboard Cite

show abstract

“…11 They appear initially in the hippocampus that is responsible for the consolidation of information flow from short-memory to long-memory and extend to the cortical gray matter killing cells in the brain and compromising their functions. 12 Neurofibrillary tangles are insoluble bundles of fibers, comprised of the intracellular aggregation of hyperphosphorylated tau (p-tau) protein, which is responsible for microtubules stabilization. The presence of these tangles is not limited to AD disease as they can also be found in other neurodegenerative disorders like Kuf's disease and subacute sclerosing panencephalitis.…”

Section: Alzheimer's Disease Pathology and Targetsmentioning

confidence: 99%

“…125 Consequently, studies over second generation anti-Aβ mAbs have taken place due to the disappointing observations from the first-generation mAbs. Gantenerumab (RG1450/RO4909832, Hoffman-La Roche), is the first fully human IgG1 antibody that targets the fibrillary Aβ form and uniquely binds the epitope that involves both, the N-terminal (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and mid-region (18)(19)(20)(21)(22)(23)(24)(25)(26)(27) residues. Hence, a folded peptide where the mid domain overlaps with the N-terminus is preferred.…”

mentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

211

175

View full text Add to dashboard Cite

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

show abstract

“…Another age-dependent microglia morphological change is the appearance of dystrophic microglia and cellular clusters [64,65]. Therefore, we analyzed the number of very apparent Iba1 + clusters (de ned as multinucleated or joined cells) in SAMP8 and SAMR1 brains at different age.…”

Section: Flow Cytometrymentioning

confidence: 99%

Senescent Accelerated Prone 8 (SAMP8) Mice as A Model of Age Dependent Neuroinflammation

Fernández

Quintana

Velasco

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Aging and age related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). The need of animal models that will allow us to understand and modulate this process is required for the scientific community. Methods: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their resistant to senescence control (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and analyzed Iba1+ clustered cells with aging. To analyse specific constant brain areas we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch), and analyzed their response to systemic LPS- driven inflammation.Results: Aged 10 month old SAMP8 mice presents many of the hallmarks of aging-dependent neuroinflammation when compared with their senescence resistant control (SAMR1); ie, increase of protein aggregates, presence of Iba1+ clusters, but not increase in the number of Iba1+ cells. We have further observed and increased of main inflammatory mediator IL-1β, and augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch) have been analyzed showing that there is not significant increase of CD45+ from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL1β) transcription is mainly enhanced in CD45+BP cells. Furthermore, we are showing that LPS-driven systemic inflammation produces inflammatory cytokines mainly in the border bMyC, sensed to a lesser extent by the BP bMyC, and is enhanced in aged SAMP8 compared to control SAMR1.Conclusion: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of main pro inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

show abstract

The relationship between the morphological subtypes of microglia and Alzheimer’s disease neuropathology

Cited by 87 publications

References 66 publications

Dystrophic microglia in late‐onset Alzheimer's disease

Dystrophic microglia in late‐onset Alzheimer's disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Senescent Accelerated Prone 8 (SAMP8) Mice as A Model of Age Dependent Neuroinflammation

Contact Info

Product

Resources

About