Inflammation and Alzheimer's disease.

Microglia may contribute to cell death in neurodegenerative diseases. We studied the activation of microglia in affected regions of Huntington disease (HD) brain by localizing thymosin β-4 (Tβ4), which is increased in reactive microglia. Activated microglia appeared in the neostriatum, cortex, and globus pallidus and the adjoining white matter of the HD brain, but not in control brain. In the striatum and cortex, reactive microglia occurred in all grades of pathology, accumulated with increasing grade, and grew in density in relation to degree of neuronal loss. The predominant morphology of activated microglia differed in the striatum and cortex. Processes of reactive microglia were conspicuous in low-grade HD, suggesting an early microglia response to changes in neuropil and axons and in the grade 2 and grade 3 cortex, were aligned with the apical dendrites of pyramidal neurons. Some reactive microglia contacted pyramidal neurons with huntingtin-positive nuclear inclusions. The early and proximate association of activated microglia with degenerating neurons in the HD brain implicates a role for activated microglia in HD pathogenesis.

Early and progressive accumulation of reactive microglia in the Huntington disease brain.

Inflammation, autotoxicity and Alzheimer disease

Abnormal accumulation of β-amyloid (Aβ) in Alzheimer's disease (AD) is associated with prominent brain inflammation. Whereas earlier studies concluded that this inflammation is detrimental, more recent animal data suggest that at least some inflammatory processes may be beneficial and promote Aβ clearance. Consistent with these observations, overproduction of transforming growth factor (TGF)-β1 resulted in a vigorous microglial activation that was accompanied by at least a 50% reduction in Aβ accumulation in human amyloid precursor protein (hAPP) transgenic mice. In a search for inflammatory mediators associated with this reduced pathology, we found that brain levels of C3, the central component of complement and a key inflammatory protein activated in AD, were markedly higher in hAPP/TGF-β1 mice than in hAPP mice. To assess the importance of complement in the pathogenesis of AD-like disease in mice, we inhibited C3 activation by expressing soluble complement receptor-related protein y (sCrry), a complement inhibitor, in the brains of hAPP mice. Aβ deposition was 2- to 3-fold higher in 1-year-old hAPP/sCrry mice than in age-matched hAPP mice and was accompanied by a prominent accumulation of degenerating neurons. These results indicate that complement activation products can protect against Aβ-induced neurotoxicity and may reduce the accumulation or promote the clearance of amyloid and degenerating neurons. These findings provide evidence for a role of complement and innate immune responses in AD-like disease in mice and support the concept that certain inflammatory defense mechanisms in the brain may be beneficial in neurodegenerative disease.

https://www.pnas.org/content/pnas/99/16/10837.full.pdf

Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice

Background We evaluated the amounts of amyloid beta (Aβ)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology. Methods Amyloid β levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects. Results Plasma Aβ levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Aβ40 than disease-free vessels. Inactivated platelets contained more Aβ peptides than activated ones. Substantially more Aβ was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Aβ. Conclusions Efforts to use plasma levels of Aβ peptides as AD biomarkers or disease-staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Aβ values is also due in part to the ability of Aβ to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Aβ plasma levels. Furthermore, the long-range impact of Aβ immunotherapy on peripheral Aβ sources should also be considered.

/pdf/amyloid-beta-peptides-in-human-plasma-and-tissues-and-their-531md7obok.pdf

Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease

Complement activation and its deposition on β-amyloid plaques in Alzheimer's Disease (AD) brains correlates with the development of AD dementia Results from immunocytochemical studies suggest that the appearance of complement activation in AD brains results in part from a direct interaction with the β-amyloid (Aβ) peptide Aβ–42, the major peptide of β-amyloid plaques To study this possibility, we exposed aggregated Aβ of different lengths to complement present in normal human serum (NHS) in vitro NHS contains two pathways for complement activation, the classical and alternative Solubilization of bound complement proteins and immunoblotting reveal that aggregated Aβ1–42 binds larger amounts of complement proteins C1q, C4, C3, C5 and C6, than aggregated Aβ1–40, Aβ1–28 and Aβ 17–43 The binding of C3, unlike CIq and C4, requires complement activation In NHS, C3 binding to aggregated Aβ1–42 occurs by both the alternative path-way and, to a lesser extent, the classical pathway The activation of C3 by bot

Complement interactions with amyloid β1–42: A nidus for inflammation in AD brains

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Complement interactions with amyloid β1–42: A nidus for inflammation in AD brains