Inflammation and Alzheimer's disease.

Background: The deposition of the amyloid β protein (Aβ) is a histopathologic hallmark of AD. The regions of the medial temporal lobe (MTL) are hierarchically involved in Aβ-deposition. Objective: To clarify whether there is a hierarchical involvement of the regions of the entire brain as well and whether there are differences in the expansion of Aβ-pathology between clinically proven AD cases and nondemented cases with AD-related pathology, the authors investigated 47 brains from demented and nondemented patients with AD-related pathology covering all phases of β-amyloidosis in the MTL (AβMTL phases) and four control brains without any AD-related pathology. Methods: Aβ deposits were detected by the use of the Campbell-Switzer silver technique and by immunohistochemistry in sections covering all brain regions and brainstem nuclei. It was analyzed how often distinct regions exhibited Aβ deposits. Results: In the first of five phases in the evolution of β-amyloidosis Aβ deposits are found exclusively in the neocortex. The second phase is characterized by the additional involvement of allocortical brain regions. In phase 3, diencephalic nuclei, the striatum, and the cholinergic nuclei of the basal forebrain exhibit Aβ deposits as well. Several brainstem nuclei become additionally involved in phase 4. Phase 5, finally, is characterized by cerebellar Aβ-deposition. The 17 clinically proven AD cases exhibit Aβ-phases 3, 4, or 5. The nine nondemented cases with AD-related Aβ pathology show Aβ-phases 1, 2, or 3. Conclusions: Aβ-deposition in the entire brain follows a distinct sequence in which the regions are hierarchically involved. Aβ-deposition, thereby, expands anterogradely into regions that receive neuronal projections from regions already exhibiting Aβ. There are also indications that clinically proven AD cases with full-blown β-amyloidosis may be preceded in early stages by nondemented cases exhibiting AD-related Aβ pathology.

Phases of Aβ-deposition in the human brain and its relevance for the development of AD

Objective: To determine the influence of type 2 diabetes mellitus on the risk of dementia and AD. Background: Both dementia and diabetes are frequent disorders in elderly people. Methods: Prospective population-based cohort study among 6,370 elderly subjects. At baseline study participants were examined for presence of diabetes mellitus. Nondemented participants were followed up, on average, for 2.1 years. Incident dementia was diagnosed using a three-step screening and comprehensive diagnostic workup. To complete the follow-up, medical files were studied of persons who could not be reexamined. We estimated relative risks with proportional hazard regression, adjusting for age, sex, and possible confounders. Results: During the follow-up, 126 patients became demented, of whom 89 had AD. Diabetes mellitus almost doubled the risk of dementia (relative risk [RR] 1.9 [1.3 to 2.8]) and AD (RR 1.9 [1.2 to 3.1]). Patients treated with insulin were at highest risk of dementia (RR 4.3 [1.7 to 10.5]). Conclusion: The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.

Diabetes mellitus and the risk of dementia The Rotterdam Study

Reactive astrocytes: cellular and molecular cues to biological function

Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model

Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases.

Lesions of Alzheimer disease are associated with low-grade but sustained inflammatory responses. Activated microglia agglomerate in the center of senile plaques. Reactive astrocytes marginate the amyloid beta-protein (A beta) deposits and extend their processes toward the center of plaques. Both microglia and astrocytes are known to secrete a wide variety of molecules involved in inflammation and are potential sources of proinflammatory elements in the brain. Dystrophic neurites occur in senile plaques with such glial reactions, suggesting the relevance of inflammatory responses to the neuronal degeneration in Alzheimer disease. Activated glial cells are, therefore, targets of anti-inflammatory therapy of Alzheimer disease. However, evidence also indicates that these cells eliminate A beta from the brain. A beta is produced continuously in both the normal and the AD brain. Under normal conditions, A beta is removed successfully before it accumulates as extracellular amyloid fibrils. Even in Alzheimer disease, a large portion of A beta may be cleared from the brain with a small portion being left and deposited as neurotoxic senile plaques. Both in vivo and in vitro studies showed the effective uptake of A beta by microglia. Before clinical application, it must be determined whether the treatment that suppresses glial activation and inflammatory responses inhibits A beta removal by glial cells.

Cell mediators of inflammation in the Alzheimer disease brain.

Thrombin accumulation in brains of patients with Alzheimer's disease.

Expression of the receptor for macrophage colony stimulating factor by brain microglia and its upregulation in brains of patients with Alzheimer's disease and amyotrophic lateral sclerosis

Hiromi Kondo

Papers

Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases.

Cell mediators of inflammation in the Alzheimer disease brain.

Thrombin accumulation in brains of patients with Alzheimer's disease.

Expression of the receptor for macrophage colony stimulating factor by brain microglia and its upregulation in brains of patients with Alzheimer's disease and amyotrophic lateral sclerosis

Expression of CD40 in the brain of Alzheimer’s disease and other neurological diseases