While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.

Parkinson disease (PD) is a neurodegenerative disorder pathologically characterized by nigrostriatal dopamine neuron loss and the postmortem presence of Lewy bodies, depositions of insoluble α-synuclein, and other proteins that likely contribute to cellular toxicity and death during the disease. Genetic and biochemical studies have implicated impaired lysosomal and mitochondrial function in the pathogenesis of PD. Transmembrane protein 175 (TMEM175), the lysosomal K+ channel, is centered under a major genome-wide association studies peak for PD, making it a potential candidate risk factor for the disease. To address the possibility that variation in TMEM175 could play a role in PD pathogenesis, TMEM175 function was investigated in a neuronal model system. Studies confirmed that TMEM175 deficiency results in unstable lysosomal pH, which led to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome, and decreased mitochondrial respiration. Moreover, TMEM175 deficiency in rat primary neurons resulted in increased susceptibility to exogenous α-synuclein fibrils. Following α-synuclein fibril treatment, neurons deficient in TMEM175 were found to have increased phosphorylated and detergent-insoluble α-synuclein deposits. Taken together, data from these studies suggest that TMEM175 plays a direct and critical role in lysosomal and mitochondrial function and PD pathogenesis and highlight this ion channel as a potential therapeutic target for treating PD.

The nuclear retinoid X receptor agonist, bexarotene, has been implicated in recovery of cognitive function in mouse models of Alzheimer's disease (AD). Since AD genetic mouse models also show abnormal neural hyperexcitability, which may play a destructive role in memory storage and retrieval, we studied whether bexarotene exerted dynamic network effects on electroencephalography cortical spike discharge rate and spectral frequency in an AD (hAPP J20 model) and non-AD (Kv1.1 null) mouse models of epilepsy. We find that oral treatment with bexarotene over 1 week acutely reduced spike discharges in both models and seizures in the Kv1.1 null mouse model without major alterations in the background frequency of brain rhythms. The effect was reversible and exhibited a similar rapid onset in hippocampal slices. While the exact mechanisms are unknown, bexarotene counteracts both amyloid-β-induced and amyloid-β-independent increases in cortical network hyperexcitability.

The nuclear retinoid X receptor agonist, bexarotene, has been implicated in recovery of cognitive function in mouse models of Alzheimer's disease (AD). Since AD genetic mouse models also show abnormal neural hyperexcitability, which may play a destructive role in memory storage and retrieval, we studied whether bexarotene exerted dynamic network effects on electroencephalography cortical spike discharge rate and spectral frequency in an AD (hAPP J20 model) and non-AD (Kv1.1 null) mouse models of epilepsy. We find that oral treatment with bexarotene over 1 week acutely reduced spike discharges in both models and seizures in the Kv1.1 null mouse model without major alterations in the background frequency of brain rhythms. The effect was reversible and exhibited a similar rapid onset in hippocampal slices. While the exact mechanisms are unknown, bexarotene counteracts both amyloid-β-induced and amyloid-β-independent increases in cortical network hyperexcitability.

Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.

Considerable evidence points to important roles for inflammation in Alzheimer's disease (AD) pathophysiology. Epidemiological studies have suggested that long-term nonsteroidal anti-inflammatory drug (NSAID) therapy reduces the risk for Alzheimer's disease; however, the mechanism remains unknown. We report that a 9-month treatment of aged R1.40 mice resulted in 90% decrease in plaque burden and a similar reduction in microglial activation. Ibuprofen treatment reduced levels of lipid peroxidation, tyrosine nitration, and protein oxidation, demonstrating a dramatic effect on oxidative damage in vivo. Fibrillar β-amyloid (Aβ) stimulation has previously been demonstrated to induce the assembly and activation of the microglial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to superoxide production through a tyrosine kinase-based signaling cascade. Ibuprofen treatment of microglia or monocytes with racemic or S-ibuprofen inhibited Aβ-stimulated Vav tyrosine phosphorylation, NADPH oxidase assembly, and superoxide production. Interestingly, Aβ-stimulated Vav phosphorylation was not inhibited by COX inhibitors. These findings suggest that ibuprofen acts independently of cyclooxygenase COX inhibition to disrupt signaling cascades leading to microglial NADPH oxidase (NOX2) activation, preventing oxidative damage and enhancing plaque clearance in the brain.

Alzheimer's disease (AD) is characterized by the deposition of β-amyloid (Aβ)-containing plaques within the brain that is accompanied by a robust microglial-mediated inflammatory response. This inflammatory response is reliant upon engagement of innate immune signaling pathways involving the toll-like receptors (TLRs). Studies assessing the roles of TLRs in AD pathogenesis have yielded conflicting results. We have assessed the roles of the TLRs through genetic inactivation of the TLR2/4 coreceptor, CD14, in a transgenic murine model of AD. Transgenic mice lacking CD14 exhibited reduced insoluble, but not soluble, levels of Aβ at 7 months of age. This corresponded with decreased plaque burden resulting from a reduction in number and size of both diffuse and thioflavin S-positive plaques and an overall reduction in the number of microglia. These findings are inconsistent with the established actions of these receptors. Moreover, loss of CD14 expression was associated with increased expression of genes encoding the proinflammatory cytokines Tnf α and Ifn γ, decreased levels of the microglial/macrophage alternative activation markers Fizz1 and Ym1 , and increased expression of the anti-inflammatory gene Il-10 . Thus, the loss of CD14 resulted in a significant change in the inflammatory environment of the brain, likely reflecting a more heterogeneous population of microglia within the brains of the animals. The reduction in plaque burden was not a result of changes in the expression of various Aβ degrading enzymes or proteins associated with Aβ clearance. These data suggest that CD14 is a critical regulator of the microglial inflammatory response that acts to modulate Aβ deposition.

The Alzheimer's disease (AD) brain is characterized by deposition of fibrillar amyloid beta (Aβ) resulting from the imbalance between the production and the clearance of soluble Aβ (sAβ) peptides. We have recently found that treatment of mouse models of AD with agonists of Liver X Receptors (LXRs), results in the proteolytic degradation and clearance of Aβ from the brain. LXRs are ligand activated transcription factors which form obligate heterodimers with RXR to form transcriptionally active complexes. These nuclear receptor complexes drive the expression of genes important for Aβ clearance, notably ApoE and the lipid transporter, ABCA1 leading to increased levels of lipidated forms of Apo in the brain. The capacity of ApoE to facilitate Aβ degradation is dependent on ApoE isoform and its lipidation status. We hypothesized that RXR agonist treatment drives sAβ degradation through enhancement of clearance of soluble species of Aβ. We assessed expression of proteins by Western blot, ELISA and immunohisotchemistry. We report that agonists of the nuclear receptors Retinoid X Receptors (RXRs) facilities sAβ clearance. We found that treatment of primary microglia with either an endogenous (9-cis retinoic acid, 9cisRA) or synthetic (bexarotene) agonist of RXRs increases the proteolytic degradation of sAβ, and this effect is correlated with an increase in expression of ABCA1 and ApoE. Importantly, treatment of murine models of AD with bexarotene is associated with a reduction in plaque burden. These data demonstrate the ligation of RXRs is sufficient to stimulate the expression of genes involved in Aβ clearance and suggests their potential therapeutic utility in treatment of AD. Importantly, the reduction in plaque burden in a murine model of AD, suggests RXR agonists may be effective in suppressing AD pathogenesis.

Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in Aβ homeostasis. We report that ApoE plays a role in facilitating the proteolytic clearance of soluble Aβ from the brain. The endolytic degradation of Aβ peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Aβ degradation extracellularly by insulin-degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Aβ degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Aβ degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Aβ load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a mechanism through which ApoE facilitates the clearance of Aβ from the brain and suggest that LXR agonists may represent a novel therapy for AD.