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The relationship between Alzheimer's disease (AD) and neuroinflammation has become stronger since the identification of several genetic risk factors related to microglial function. Though the role of microglial cells in the development/progression of AD is still unknown, a dysfunctional response has recently gained support. In this sense, we have reported an attenuated microglial activation associated to amyloid plaques in the hippocampus of AD patients, including a prominent degenerative process of the microglial population in the dentate gyrus, which was in contrast to the exacerbated microglial response in amyloidogenic models. This microglial degeneration could compromise their normal role of surveying the brain environment and respond to the damage. Here, we have further analyzed the phenotypic profile displayed by the damage-associated microglial cells by immunostaining and qPCR in the hippocampus of postmortem samples of AD patients (Braak V-VI) and control cases (Braak 0-II). Damage-associated microglial cells of Braak V-VI individuals were clustered around amyloid plaques and expressed Iba1, CD68, Trem2, TMEM119 and CD45high. A subset of these cells also expressed ferritin. On the contrary, these microglia down-regulated homeostatic markers, such as Cx3cr1 and P2ry12. The homeostatic and ramified microglial cells of non-demented Braak II cases were characterized by Iba1, CX3CR1, P2ry12, TMEM119 and CD45low expression. The dynamic of the microglial molecular phenotypes associated to AD pathology needs to be considered for better understand the disease complexity and, therefore, guarantee clinical success. Correcting dysregulated brain inflammatory responses might be a promising avenue to prevent/slow cognitive decline. ; Universidad de Málaga. Campus de excelencia Internacional-Andalucía Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union.

The continuing failure to develop an effective treatment for Alzheimer's disease (AD) reveals the complexity for this pathology. Increasing evidence indicates that neuroinflammation involving particularly microglial cells contributes to AD pathogenesis. The actual view, based on the findings in APP based models, gives a cytotoxic/proinflammatory role to activated microglia. However, we have previously reported a limited activation and microglial degeneration in the hippocampus of AD patients in contrast with that observed in amyloidogenic models. Here, we evaluated the microglial response in a different region of AD brains, the frontal cortex. Post mortem tissue from controls (Braak 0-II) and AD patients (Braak V-VI) including familial cases, were obtained from Spain Neurological Tissue Banks. Cellular (immunohistochemistry and image analysis) and molecular (qPCR and western blots) approaches were performed. Frontal cortex of AD patients (Braak V-VI) showed strong microglial activation similar to that observed in amyloidogenic mice. These strongly activated microglial cells, predominantly located surrounding amyloid plaques, could drive the AD pathology and, in consequence, could be implicated in the pathology progression. Furthermore, different microglial responses were observed between sporadic and familial AD cases. These findings in the frontal cortex were highly in contrast to the attenuated activation and degenerative morphology displayed by microglial cells in the hippocampus of AD patients. Regional differences in the microglial response suggest different functional states of microglial cells in a region-specific manner. All together, these data provide a better understanding of the immunological mechanisms underlying AD progression and uncover new potential therapeutic targets to fight this devastating neurodegenerative disease. ; Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union

Amyloid-beta (Abeta) peptide deposits and hyperphosphorylated tau protein (phospho-tau) accumulate in Alzheimer's disease (AD) brains. These abnormal protein aggregates leads to glial activation, synaptic dysfunction, neuronal loss and cognitive decline. While microglial response has mostly been analyzed in relation to Abeta accumulation, little is still known about inflammatory processes associated with tau pathology. Microglial reactivity and defective glial responses have been involved in these proteinopathies. Our aim is to clarify the effects of Abeta and tau separately, in order to improve the comprehension of their differential contribution to neuroinflammation and neurodegeneration. We compared the progression of these processes in an amyloidogenic AD model (APPSL/PS1M146L) and two different models of tauopathy (ThyTau22 and hP301S) from 2 to 18 months of age. Accumulation of aggregated proteins was assessed using specific anti- Abeta and phospho-tau antibodies. Inflammatory response was studied using a battery of microglial markers (Iba1, CD45, CD68, Trem2 and Gal-3). In the hippocampus of these models, Tau and Abeta pathologies initiated as early as 2 months of age and increased progressively with aging. Neuritic plaques induced a strong microglial activation associated to plaques in APP/PS1 mice. Interestingly, inflammatory markers and microglial reactivity were barely increased in the hippocampus of ThyTau mice in contrast to not only APP/PS1, but also to P301S mice, which displayed a prominent microglial response. Deciphering the specific effects of Abeta, tau and their different toxic species, would indeed enable the development of novel therapeutic strategies and drugs targeting neuroinflammatory pathways related to these proteinopathies. ; Universidad de Málaga. Campus de excelencia Andalucía-Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union, and by grant PPIT.UMA.B1.2017/26 (RS-V).

AIMS: Amyloid-beta (Abeta) deposits and intraneuronal hyperphosphorylated tau are major pathological hallmarks of Alzheimer's disease (AD). The coexistence of these aggregates in AD brains leads to synaptic dysfunction, neuronal loss and cognitive decline. Failures in protein homeostasis, along with defective glial responses, have been identified as pathological mechanisms linked to this disorder. Thus, our main objective is to better understand the differential impact of Abeta- and tau-aggregates to these processes in the hippocampus of AD models. METHODS: We analyzed APP- (APPSL/PS1M146L) and Tau- (ThyTau22 and hP301S) based models from 2 to 18 months of age. Tau and Abeta pathologies were assessed by western blotting and immunohistochemistry. Confocal microscopy was used to study microglia/aggregates relationship. Levels of synaptic proteins, autophagy and inflammatory markers were determined by quantitative PCR, WB and immunohistochemistry. RESULTS: Tau and Abeta pathologies initiated as early as 2 months of age and increased progressively with aging. Even though only APP/PS1 hippocampus showed dystrophic neurites positive to proteostatic and presynaptic markers, their protein levels were altered in both types of models from 6-9 months compared to age-matched WT mice. Inflammatory markers and microglial reactivity were barely increased in the hippocampus of ThyTau mice in contrast to P301S and APP/PS1 mice which displayed a prominent microglial response. CONCLUSIONS: Clarifying the effects of Abeta and tau separately would indeed enable the development of novel therapeutic strategies and drugs targeting pathways related to these proteinopathies. Supported by grants FIS PI15/00796 and PI15/00957 co-financed by FEDER funds from European Union, by Junta de Andalucia Proyecto de Excelencia CTS385 2035 and by grant PPIT.UMA.B1/2017.26 ; Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

In Alzheimer's disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aβ) deposits. However, the effect of microtubule stabilizing agents on Aβ pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aβ accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aβ levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aβ pathology. ; This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI15/00796 and PI18/01557 (both to AG), PI15/00957 and PI18/01556 (both to JV), and CIBERNED (CB06/05/1116 to AG and CB06/05/0094 to JV); by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). JJFV and CMC were supported by FPU PhD fellowships (Spanish Ministry of Science, Innovation and Universities). RSV held a postdoctoral contract from Malaga University. IMG is recipient of a senior postdoctoral contract from Ramon y Cajal Program (Spain Government). ; Yes