Minocycline Reduces Microglial Activation and Improves Behavioral Deficits in a Transgenic Model of Cerebral Microvascular Amyloid

Abstract

Cerebral microvascular amyloid ␤ protein (A␤) deposition and associated neuroinflammation is increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease and related cerebral amyloid angiopathy disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human A␤ precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits and exhibit robust neuroinflammation. In the present study, we investigated the effect of the anti-inflammatory drug minocycline on A␤ accumulation, neuroinflammation, and behavioral deficits in Tg-SwDI mice. Twelve-month-old mice were treated with saline or minocycline by intraperitoneal injection every other day for a total of 4 weeks. During the final week of treatment, the mice were tested for impaired learning and memory. Brains were then harvested for biochemical and immunohistochemical analysis. Minocycline treatment did not alter the cerebral deposition of A␤ or the restriction of fibrillar amyloid to the cerebral microvasculature. Similarly, minocycline-treated Tg-SwDI mice exhibited no change in the levels of total A␤, the ratios of A␤40 and A␤42, or the amounts of soluble, insoluble, or oligomeric A␤ compared with the saline-treated control Tg-SwDI mice. In contrast, the numbers of activated microglia and levels of interleukin-6 were significantly reduced in minocycline-treated Tg-SwDI mice compared with saline-treated Tg-SwDI mice. In addition, there was a significant improvement in behavioral performance of the minocycline-treated Tg-SwDI mice. These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of A␤.

Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

“…F/T, Frontotemporal cortex. fibrillar amyloid, but not diffuse A␤ plaque deposits, in Tg-SwDI/ muAPOE mice (Miao et al, 2005a,b;Fan et al, 2007). Because the current results clearly show that Tg-SwDI mice on human APOE backgrounds shift the distribution of fibrillar amyloid from the microvascular deposits to parenchymal plaques, we investigated whether this altered the spatial accumulation of neuroinflammatory reactive astrocytes and activated microglia.…”

“…In Tg-SwDI/muAPOE mice, activated microglia are tightly associated with the development of cerebral microvascular fibrillar amyloid (Miao et al, 2005a;Fan et al, 2007;Xu et al, 2007). In these mice, the abundant parenchymal diffuse A␤ deposits do not appear to promote microglial activation.…”

“…The finding that Tg-SwDI mice accumulate extensive cerebral microvascular A␤, despite low levels of transgene-directed human A␤PP expression, appears to primarily result from ineffective clearance of Dutch/Iowa mutant A␤ from brain across the blood-brain barrier into the circulation (Davis et al, , 2006Deane et al, 2004). In Tg-SwDI mice, cerebral microvascular amyloid deposition is intimately linked with a robust neuroinflammatory response, highlighted by localized strong microglial activation and deficits in spatial learning and memory (Miao et al, 2005b;Fan et al, 2007;Xu et al, 2007).…”

The Neuroimmune Transcriptome and Alcohol Dependence: Potential for Targeted Therapies

“…One potential drug already being investigated is (+)-naloxone, which inhibits TLR4-mediated microglial activation and decreases proinflammatory cytokine expression [63]. Another microglia-related drug is minocycline, which reduces microglial and neuroimmune activation [64]. Minocycline also decreases ethanol consumption, albeit by an unknown mechanism [65].…”

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…For addiction, in particular, studies have highlighted the glutamatergic and DA effects of minocycline, which in turn have been implicated in addiction etiology (Kalivas & Volkow, 2005). In addition, the effects of minocycline on neuroimmune and cytokine expression have been emphasized as potential therapeutic targets for this medication (Fan et al, 2007;Mishra & Basu, 2008). Preclinical studies have found that minocycline attenuated NMDA receptor antagonist-induced cognitive impairment in rodents (Fujita et al, 2008;Munzar, Li, Nicholson, Wiley, & Balster, 2002).…”