Mark W. Albers

Tau positron emission tomographic imaging in aging and early Alzheimer disease

Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease‐modifying therapies.

Tau PET imaging in aging and early Alzheimer's disease

Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease‐modifying therapies.

At the interface of sensory and motor dysfunctions and Alzheimer's disease

Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimers disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age‐related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled “Sensory and Motor Dysfunctions in Aging and AD.” The scientific sessions of the workshop focused on age‐related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory‐motor deficits in AD may enhance patient function as AD progresses.

The precision of axon targeting of mouse olfactory sensory neurons requires the BACE1 protease

The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is necessary to generate the Aβ peptide, which is implicated in Alzheimers disease pathology. Studies show that the expression of BACE1 and its protease activity are tightly regulated, but the physiological function of BACE1 remains poorly understood. Recently, numerous axon guidance proteins were identified as potential substrates of BACE1. Here, we examined the consequences of loss of BACE1 function in a well-defined in vivo model system of axon guidance, mouse olfactory sensory neurons (OSNs). The BACE1 protein resides predominantly in proximal segment and the termini of OSN axons, and the expression of BACE1 inversely correlates with odor-evoked neural activity. The precision of targeting of OSN axons is disturbed in both BACE1 null and, surprisingly, in BACE1 heterozygous mice. We propose that BACE1 cleavage of axon guidance proteins is essential to maintain the connectivity of OSNs in vivo.

Molecular recognition of immunophilins and immunophilin-ligand complexes

Abstract Immunophilin-ligand complexes have been used to identify a previously unknown step in Ca2+-dependent signal transduction pathways. This Report, which we dedicate to Professor Harry H. Wasserman, describes structural and mechanistic aspects of immunophilin research.

Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo

The Aβ peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimers disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here, we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) prior to the onset of plaques. Expression of hAPPsw exclusively in olfactory sensory neurons (OSNs) also perturbs connectivity with associated reductions in odor-evoked gene expression and olfactory acuity. By contrast, OSN axons project correctly in mice overexpressing wild type human APP throughout the brain and in mice overexpressing human APPmv, a missense mutation that reduces Aβ production, exclusively in OSNs. Furthermore, expression of Aβ40 or Aβ42 solely in the olfactory epithelium disrupts OSN axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human Aβ.

Odor identification and Alzheimer disease biomarkers in clinically normal elderly.

Objectives: Our objective was to investigate cross-sectional associations between odor identification ability and imaging biomarkers of neurodegeneration and amyloid deposition in clinically normal (CN) elderly individuals, specifically testing the hypothesis that there may be an interaction between amyloid deposition and neurodegeneration in predicting odor identification dysfunction. Methods: Data were collected on 215 CN participants from the Harvard Aging Brain Study. Measurements included the 40-item University of Pennsylvania Smell Identification Test and neuropsychological testing, hippocampal volume (HV) and entorhinal cortex (EC) thickness from MRI, and amyloid burden using Pittsburgh compound B (PiB) PET. A linear regression model with backward elimination (p < 0.05 retention) evaluated the cross-sectional association between the University of Pennsylvania Smell Identification Test and amyloid burden, HV, and EC thickness, assessing for effect modification by PiB status. Covariates included age, sex, premorbid intelligence, APOE ε4 carrier status, and Boston Naming Test. Results: In unadjusted univariate analyses, worse olfaction was associated with decreased HV (p < 0.001), thinner EC (p = 0.003), worse episodic memory (p = 0.03), and marginally associated with greater amyloid burden (binary PiB status, p = 0.06). In the multivariate model, thinner EC in PiB-positive individuals (interaction term) was associated with worse olfaction (p = 0.02). Conclusions: In CN elderly, worse odor identification was associated with markers of neurodegeneration. Furthermore, individuals with elevated cortical amyloid and thinner EC exhibited worse odor identification, elucidating the potential contribution of olfactory testing to detect preclinical AD in CN individuals.

Synaptic Plasticity Defect Following Visual Deprivation in Alzheimer's Disease Model Transgenic Mice

Amyloid-β (Aβ)-induced changes in synaptic function in experimental models of Alzheimers disease (AD) suggest that Aβ generation and accumulation may affect fundamental mechanisms of synaptic plasticity. To test this hypothesis, we examined the effect of APP overexpression on a well characterized, in vivo, developmental model of systems-level plasticity, ocular dominance plasticity. Following monocular visual deprivation during the critical period, mice that express mutant alleles of amyloid precursor protein (APPswe) and Presenilin1 (PS1dE9), as well as mice that express APPswe alone, lack ocular dominance plasticity in visual cortex. Defects in the spatial extent and magnitude of the plastic response are evident using two complementary approaches, Arc induction and optical imaging of intrinsic signals in awake mice. This defect in a classic paradigm of systems level synaptic plasticity shows that Aβ overexpression, even early in postnatal life, can perturb plasticity in cerebral cortex, and supports the idea that decreased synaptic plasticity due to elevated Aβ exposure contributes to cognitive impairment in AD.

Hepatotrophic properties in dogs of human FKBP, the binding protein for FK506 and rapamycin

Cyclosporine and FK506 have been shown with two experimental models to influence liver structure, function, and the capacity for regeneration. Both drugs augment the liver regeneration in rats that is the normal response to partial hepatectomy (1). In addition, the increase in hepatocyte replication that is caused by portacaval shunt in dogs is more than doubled by intrahepatic infusion of these drugs via the tied-off central portal vein. Also, the atrophy and organelle disruption caused by portacaval shunt is prevented (2, 3). Immune modulation of lymphocytes and NK cells as an explanation for these so-called “hepatotrophic” effects has been ruled out by direct experimentation in nude rats (4). The foregoing findings, as well as observations of manifold metabolic effects in patients treated either with FK506 or with cyclosporine, have led to a hypothesis that these drugs modify signal transduction in a variety of cells, not limited to those of the immune system (3, 5). Consistent with the hypothesis is the recent demonstration that FK506 and cyclosporine inhibit signaling processes in the mast cell at concentrations similar to those used to block signaling pathways in T cells (6; also Schreiber SL, et al., unpublished observations). Central to the signal transduction hypothesis was the discovery that the cytosolic receptors for FK506 and rapamycin (FK506-binding protein, FKBP)* and cyclosporine (cyclophilin) are distinct proteins that exhibit peptidyl-prolyl cis trans isomerase (rotamase) activity (7, 8). Rotamases have been shown to facilitate protein folding (9, 10) and to catalyze the interconversion of rotamers of peptidyl-prolyl bonds in vitro (11, 12). However, the inhibition of this enzymatic activity is not related to the action of these drugs in the T cell (13) or the mast cell (Schreiber SL, Hohman RJ, et al., unpublished observations). Instead, these proteins are envisioned as members of a class of small molecular weight cytoplasmic proteins (collectively called immunophilins) that modulate a wide variety of calcium-dependent signal transduction pathways by forming complexes with immunosuppressive drugs (13, 14). The potential importance and pleiotropism of the immunophilin network is emphasized by the ubiquitous distribution of cyclophilin as detected by immunocytochemical techniques in the cytoplasm of virtually all cells in the body, and in the nuclei of some (15, 16). How the immunophilins are activated by immunosuppressive agents is not known, nor is it known if modulation of the immunophilin’s activity requires binding of an exogenous (drug) or endogenous ligand. With the cloning and overexpression of FKBP in bacteria (17), it became possible to test the intrinsic activity of FKBP, free of drug. Briefly, with the use of the expression cassette polymerase chain reaction (18), the proper sequences were added to the FKBP cDNA that allow for its overexpression in E. coli. Following a simple purification protocol (17), recombinant human FKBP was demonstrated to be pure by SDS-PAGE analysis. The recombinant FKBP was dissolved in normal saline modified by the addition of 5 mM ammonium acetate and 5 mg/L bovine serum albumin (to prevent adhesion to the plastic tubing). After performing completely diverting portacaval shunt, an infusion catheter was inserted into the tied-off left portal vein for pump-driven constant infusion of the FKBP over the next 4 days. At the end of 4 days, the animals were injected with 0.2 mci/kg intravenous 3H-thymidine (New England Nuclear, Boston) and killed 2 hr later. Specimens were obtained for comparison of the hepatocytes in the left (infused) and right (not infused) liver lobes using previously described morphometric and autoradiographic techniques (3, 19). Autoradiography was carried out with Kodak NTB2 liquid emulsion with an exposure time of at least 30 days. The number of replicating hepatocytes as an index of hepatocyte regeneration was determined by counting the number of 3H-thymidine-labeled nuclei per 1000 hepatocytes. The size of individual hepatocytes (index of hypertrophy or atrophy) was determined by tracing out at least 500 midzonal liver cells projected on standard-thickness paper, cutting out the individual silhouettes, and weighing each. This method has been shown to be accurate for determining hepatocyte cell size and has been validated by planimetry and by studies of unicellular organisms, the size of which has been determined directly. An insulin infusion, which we use to verify the integrity of the test system (2, 19), prevented the usual hepatocyte atrophy and increased the hepatocyte proliferation in the directly infused lobes only (Table 1). TABLE 1 Effect of cloned FKBP infusion in left portal branch for 4 days after canine ECK fistula Because it has been assumed that immunophilins are activated by binding with a drug or other ligands, it was suspected when these experiments were planned that the cloned FKBP would be inert. Instead, a substantial dose-related hepatotrophic response was caused (Table 1), with partial prevention of the hepatocyte atrophy and augmentation of hepatocyte proliferation in the directly infused lobes only. This is the first demonstration of a physiologic action of an unbound immunophilin, and one with important implications. One possibility for resolving the discrepancy that a cytosolic protein has a physiologic activity outside of the cell is that there may be a secretory variant of the FKBP family that has hepatotrophic effects. Thus, one could argue that the extracellular concentration of this putative hormone has been increased by infusing a closely related protein into the liver. An alternative possibility is that the recombinant FKBP bound with a natural circulating ligand, and that the complex activated regulatory growth factors, possibly including cytokines.

Tau-amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid-induced disruption of axonal projections and exacerbated axonal pathology.

Early observations of the patterns of neurofibrillary tangles and amyloid plaques in Alzheimers disease suggested a hierarchical vulnerability of neurons for tangles, and a widespread nonspecific pattern of plaques that nonetheless seemed to correlate with the terminal zone of tangle‐bearing neurons in some instances. The first neurofibrillary cortical lesions in Alzheimers disease occur in the entorhinal cortex, thereby disrupting the origin of the perforant pathway projection to the hippocampus, and amyloid deposits are often found in the molecular layer of the dentate gyrus, which is the terminal zone of the entorhinal cortex. We modeled these anatomical changes in a transgenic mouse model that overexpresses both P301L tau (uniquely in the medial entorhinal cortex) and mutant APP/PS1 (in a widespread distribution) to examine the anatomical consequences of early tangles, plaques, or the combination. We find that tau uniformly occupies the terminal zone of the perforant pathway in tau‐expressing mice. By contrast, the addition of amyloid deposits in this area leads to disruption of the perforant pathway terminal zone and apparent aberrant distribution of tau‐containing axons. Moreover, human P301L tau‐containing axons appear to increase the extent of dystrophic axons around plaques. Thus, the presence of amyloid deposits in the axonal terminal zone of pathological tau‐containing neurons profoundly impacts their normal connectivity. J. Comp. Neurol. 521:4236–4248, 2013.