The Unifying Hypothesis of Alzheimer’s Disease: Heparan Sulfate Proteoglycans/Glycosaminoglycans Are Key as First Hypothesized Over 30 Years Ago

The updated “Unifying Hypothesis of Alzheimer’s disease” (AD) is described that links all the observed neuropathology in AD brain (i.e., plaques, tangles, and cerebrovascular amyloid deposits), as well as inflammation, genetic factors (involving ApoE), “AD-in-a-Dish” studies, beta-amyloid protein (Aβ) as a microbial peptide; and theories that bacteria, gut microflora, gingivitis and viruses all play a role in the cause of AD. The common link is the early accumulation of heparan sulfate proteoglycans (HSPGs) and heparan sulfate glycosaminoglycans (GAGs). HS GAG accumulation and/or decreased HS GAG degradation is postulated to be the key initiating event. HS GAGs and highly sulfated macromolecules induce Aβ 1–40 (but not 1–42) to form spherical congophilic maltese-cross star-like amyloid core deposits identical to those in the AD brain. Heparin/HS also induces tau protein to form paired helical filaments (PHFs). Increased sulfation and/or decreased degradation of HSPGs and HS GAGs that occur due to brain aging leads to the formation of plaques and tangles in AD brain. Knockout of HS genes markedly reduce the accumulation of Aβ fibrils in the brain demonstrating that HS GAGs are key. Bacteria and viruses all use cell surface HS GAGs for entry into cells, including SARS-CoV-2. Bacteria and viruses cause HS GAGs to rapidly increase to cause near-immediate aggregation of Aβ fibrils. “AD-in-a-dish” studies use “Matrigel” as the underlying scaffold that spontaneously causes plaque, and then tangle formation in a dish. Matrigel mostly contains large amounts of perlecan, the same specific HSPG implicated in AD and amyloid disorders. Mucopolysaccharidoses caused by lack of specific HS GAG enzymes lead to massive accumulation of HS in lysosomal compartments in neurons and contribute to cognitive impairment in children. Neurons full of HS demonstrate marked accumulation and fibrillization of Aβ, tau, α-synuclein, and prion protein (PrP) in mucopolysaccharidosis animal models demonstrating that HS GAG accumulation is a precursor to Aβ accumulation in neurons. Brain aging leads to changes in HSPGs, including newly identified splice variants leading to increased HS GAG sulfation in the AD brain. All of these events lead to the new “Unifying Hypothesis of Alzheimer’s disease” that further implicates HSPGs /HS GAGs as key (as first hypothesized by Snow and Wight in 1989).

The Impact of Federal Home Loan Bank (FHLB) Advances on Small Business Lending by Community Banks—2010–2016

In this paper, we examine the relationship between small business loan growth and growth in core deposits and Federal Home Loan Banks (FHLBs) advances from 2010 to 2016. Controlling for other effects, we find that the relationships between small business loan growth is positively and significantly related to both FHLB advance growth and core deposit growth, with the coefficient on advance growth being significantly larger than the coefficient on core deposits over the entire sample period. We also tested whether this relationship changed after 2014:3 reflecting the Federal Reserve’s relaxation of the regulatory burden on smaller banks. We find that the relationship between loan growth and core deposit growth became more positive after the change, but the relationship between loan growth and FHLB advance growth did not. As a result, we could no longer reject the hypothesis that the coefficient on core deposit growth was equal to the coefficient on FHLB advance growth after 2014:3. This provides some empirical support that the regulatory changes in the Dodd-Frank Wall Street Reform and Consumer Protection Act of 2010 (DFA) influenced small business lending by strengthening the impact of the growth in core deposits on the growth of small business lending, complementing the work of Bordo and Duca (2018) that changes in DFA had some unintended negative consequences for lending to small businesses. It also suggests that lowering the regulatory burden faced by community banks (which have a larger proportion of core deposits to total assets than non-community banks) could improve the incentive to increase small business lending. It also implies that FHLB advances remain an important funding tool at the margin to give commercial banking organizations greater liquidity and flexibility in funding their balance sheets.

Lake basin closure and episodic inflow as recorded by radiogenic Sr isotopes: Eocene Green River Formation in the Piceance Creek Basin, Colorado

Lacustrine basins are excellent archives of lake evolution, and deposits record the uplift and weathering histories of the surrounding terrain. The application of Sr isotopes has been tested in several lacustrine basins, both modern and ancient, based on the premise that lakes are well mixed, and shifting Sr isotopes may suggest changes in lake provenance. In the Eocene lacustrine Green River Formation in the Piceance Creek Basin of Colorado, Sr isotope analysis of carbonate mudstones indicates that radiogenic Sr in the center of the Piceance lake decreased during the evolution of the lake, from 52.8–48.4 Ma. Because deposition in the basin center occurred away from the influence of episodic alluvial inflow at the basin margin, Sr isotope evolution in the Piceance lake after basin closure is recorded in the John Savage #24-1 core deposits, not the Anvil Points deposits. Sr isotope analysis of carbonate mudstones at Anvil Points below 55 m shows fluctuating radiogenic Sr values that record episodic inflow from the White River Uplift. This inflow is responsible for the difference in radiogenic Sr trends recorded between the basin center and margin. Above 55 m, fluctuating Sr isotope values at Anvil Points record episodic inflow from the White River Uplift, without inflow of Paleozoic and Mesozoic carbonates. The boundary at 55 m records the hydrologic closure of the Uinta and Piceance lakes around 52 Ma, when lake level lowered beneath the basin sill and the lakes were no longer connected across the Douglas Creek Arch. A significant increase in radiogenic Sr across the 55-m-boundary records this transition from open to closed hydrology, reflecting a loss of dissolved Sr sourced from Paleozoic and Mesozoic carbonates.