THE PATHOPHYSIOLOGY of Alzheimer disease (AD) has many connections with cholesterol metabolism. Epidemiological studies show that patients with elevated cholesterol levels have an increased risk of AD.^1,2 One of the major risk factors for AD, is apolipoprotein E type 4 (APOE4), which is a cholesterol transport protein.^3,4 Patients carrying the APOE4 polymorphism have elevated cholesterol levels, although at least part of the risk for AD seems to derive from factors unrelated to cholesterol level.² Patients with the APOE4 polymorphism also have increased risk of cardiovascular disease, and epidemiological studies show that patients with cardiovascular disease have an increased risk of AD.⁵ A second putative risk factor for AD, α₂-macroglobulin, binds to the same receptor as does APOE4.⁶ This receptor, the lipoprotein receptor–related protein, is important for cellular uptake of cholesterol.⁷ Cholesterol also effects the biology of β-amyloid (Aβ). β-αmyloid is a protein that accumulates in the affected brains of patients with AD and is thought to cause the neurodegeneration underlying AD.⁸ Production of the Aβ peptide is increased by cholesterol in some cells.⁹ These multiple links suggest a potentially important relation between cholesterol and AD.

Tar DNA Binding Protein-43 (TDP-43) is a principle component of inclusions in many cases of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 resides predominantly in the nucleus, but in affected areas of ALS and FTLD-U central nervous system, TDP-43 is aberrantly processed and forms cytoplasmic inclusions. The mechanisms governing TDP-43 inclusion formation are poorly understood. Increasing evidence indicates that TDP-43 regulates mRNA metabolism by interacting with mRNA binding proteins that are known to associate with RNA granules. Here we show that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein - RNA complexes. Under stressful conditions SGs are generated by the reversible aggregation of prion-like proteins, such as TIA-1, to regulate mRNA metabolism and protein translation. We also show that disease-linked mutations in TDP-43 increased TDP-43 inclusion formation in response to stressful stimuli. Biochemical studies demonstrated that the increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation. We observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. Finally, using Sudan black to quench endogenous autofluorescence, we also demonstrate that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. These data provide support for accumulating evidence that TDP-43 participates in the SG pathway.

Objective To investigate whether angiotensin receptor blockers protect against Alzheimer’s disease and dementia or reduce the progression of both diseases. Design Prospective cohort analysis. Setting Administrative database of the US Veteran Affairs, 2002-6. Population 819 491 predominantly male participants (98%) aged 65 or more with cardiovascular disease. Main outcome measures Time to incident Alzheimer’s disease or dementia in three cohorts (angiotensin receptor blockers, lisinopril, and other cardiovascular drugs, the “cardiovascular comparator”) over a four year period (fiscal years 2003-6) using Cox proportional hazard models with adjustments for age, diabetes, stroke, and cardiovascular disease. Disease progression was the time to admission to a nursing home or death among participants with pre-existing Alzheimer’s disease or dementia. Results Hazard rates for incident dementia in the angiotensin receptor blocker group were 0.76 (95% confidence interval 0.69 to 0.84) compared with the cardiovascular comparator and 0.81 (0.73 to 0.90) compared with the lisinopril group. Compared with the cardiovascular comparator, angiotensin receptor blockers in patients with pre-existing Alzheimer’s disease were associated with a significantly lower risk of admission to a nursing home (0.51, 0.36 to 0.72) and death (0.83, 0.71 to 0.97). Angiotensin receptor blockers exhibited a dose-response as well as additive effects in combination with angiotensin converting enzyme inhibitors. This combination compared with angiotensin converting enzyme inhibitors alone was associated with a reduced risk of incident dementia (0.54, 0.51 to 0.57) and admission to a nursing home (0.33, 0.22 to 0.49). Minor differences were shown in mean systolic and diastolic blood pressures between the groups. Similar results were observed for Alzheimer’s disease. Conclusions Angiotensin receptor blockers are associated with a significant reduction in the incidence and progression of Alzheimer’s disease and dementia compared with angiotensin converting enzyme inhibitors or other cardiovascular drugs in a predominantly male population.

The accumulation of aggregated α-synuclein is thought to contribute to the pathophysiology of Parkinson's disease, but the mechanism of toxicity is poorly understood. Recent studies suggest that aggregated proteins cause toxicity by inhibiting the ubiquitin-dependent proteasomal system. In the present study, we explore how α-synuclein interacts with the proteasome. The proteasome exists as a 26 S and a 20 S species. The 26 S proteasome is composed of the 19 S cap and the 20 S core. Aggregated α-synuclein strongly inhibited the function of the 26 S proteasome. The IC₅₀ of aggregated α-synuclein for ubiquitin-independent 26 S proteasomal activity was 1 nm. Aggregated α-synuclein also inhibited 26 S ubiquitin-dependent proteasomal activity at a dose of 500 nm. In contrast, the IC₅₀ of aggregated α-synuclein for 20 S proteasomal activity was > 1 ॖm. This suggests that aggregated α-synuclein selectively interacts with the 19 S cap. Monomeric α-synuclein also inhibited proteasomal activity but with lower affinity and less potency. Recombinant monomeric α-synuclein inhibited the activity of the 20 S proteasomal core with an IC₅₀ > 10 ॖm, exhibited no inhibition of 26 S ubiquitin-dependent proteasomal activity at doses up to 5 ॖm, and exhibited only partial inhibition (507) of the 26 S ubiquitin-independent proteasomal activity at doses up to 10 mm. Binding studies demonstrate that both aggregated and monomeric α-synuclein selectively bind to the proteasomal protein S6′, a subunit of the 19 S cap. These studies suggest that proteasomal inhibition by aggregated α-synuclein could be mediated by interaction with S6′.