The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes.

The amyloid precursor protein (APP) has occupied a central position in Alzheimer's disease (AD) pathophysiology, in large part due to the seminal role of amyloid-ß peptide (Aß), a proteolytic fragment derived from APP. Although the contribution of Aß to AD pathogenesis is accepted by many in the research community, recent studies have unveiled a more complicated picture of APP's involvement in neurodegeneration in that other APP-derived fragments have been shown to exert pathological influences on neuronal function. However, not all APP-derived peptides are neurotoxic, and some even harbor neuroprotective effects. In this review, we will explore this complex picture by first discussing the pleiotropic effects of the major APP-derived peptides cleaved by multiple proteases, including soluble APP peptides (sAPPα, sAPPß), various C- and N-terminal fragments, p3, and APP intracellular domain fragments. In addition, we will highlight two interesting sequences within APP that likely contribute to this duality in APP function. First, it has been found that caspase-mediated cleavage of APP in the cytosolic region may release a cytotoxic peptide, C31, which plays a role in synapse loss and neuronal death. Second, recent studies have implicated the -YENPTY- motif in the cytoplasmic region as a domain that modulates several APP activities through phosphorylation and dephosphorylation of the first tyrosine residue. Thus, this review summarizes the current understanding of various APP proteolytic products and the interplay among them to gain deeper insights into the possible mechanisms underlying neurodegeneration and AD pathophysiology.

Prevalence of Alpha-1 Antitrypsin Deficiency, Self-Reported Behavior Change, and Health Care Engagement Among Direct-to-Consumer Recipients of a Personalized Genetic Risk Report.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition that predisposes to emphysema, cirrhosis, panniculitis, and vasculitis. Underrecognition has prompted efforts to enhance early detection and testing of at-risk individuals. Direct-to-consumer (DTC) genetic testing represents an additional method of detection. RESEARCH QUESTION: The study addressed three questions: (1) Does a DTC testing service identify previously undetected individuals with AATD? (2) What was the interval between initial AATD-related symptoms and initial diagnosis of AATD in such individuals? and (3) What was the behavioral impact of learning about a new diagnosis of AATD through a DTC test? STUDY DESIGN AND METHODS: In this cross-sectional study, 195,014 individuals responded to a survey within the 23andMe, Inc. research platform. RESULTS: Among 195,014 study participants, the allele frequency for the PI∗S and PI∗Z AATD variants was 21.6% (6.5% for PI∗Z and 15.1% for PI∗S); 0.63% were PI∗ZZ, half of whom reported having a physician confirm the diagnosis. Approximately 27% of those with physician-diagnosed AATD reported first becoming aware of AATD through the DTC test. Among those newly aware participants, the diagnostic delay interval was 22.3 years. Participants frequently shared their DTC test results with health care providers (HCPs) and the reported impact of learning a diagnosis of AATD was high. For example, 51.1% of PI∗ZZ individuals shared their DTC result with an HCP. The OR for PI∗ZZ smokers to report smoking reduction as a result of receiving the DTC result was 1.7 (95% CI = 1.4-2.2) compared with those without a Z allele and for reduced alcohol consumption this was 4.0 (95% CI = 2.6-5.9). INTERPRETATION: In this largest available report on DTC testing for AATD, this test, in combination with clinical follow-up, can help to identify previously undiagnosed AATD patients. Moreover, receipt of the DTC AATD report was associated with positive behavior change, especially among those with risk variants.

CYP2C19 Allele Frequencies in Over 2.2 Million Direct-to-Consumer Genetics Research Participants and the Potential Implication for Prescriptions in a Large Health System.

Understanding the prevalence of clinically relevant pharmacogenetic variants using large unselected populations is critical for gauging the potential clinical impact of widespread preemptive pharmacogenetic testing. To this end, we assessed the frequencies and ethnic distribution of the three most common CYP2C19 alleles (*2, *3, and *17) in 2.29 million direct-to-consumer genetics research participants (23andMe, Sunnyvale, CA). The overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17, and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased-function or no-function CYP2C19 allele. To better understand how this high frequency might impact a real patient population, we examined the prescription rates (Rx) of high-pharmacogenetic-risk medications metabolized by CYP2C19 using the University of California at San Francisco (UCSF) health system's anonymized database of over 1.25 million patients. Between 2012 and 2019, a total of 151,068 UCSF patients (15.8%) representing 5 self-reported ethnicities were prescribed one or more high-pharmacogenetic-risk CYP2C19 medications: proton pump inhibitors (145,243 Rx), three selective serotonin reuptake inhibitor antidepressants (54,463 Rx), clopidogrel (14,376 Rx), and voriconazole (2,303 Rx).

Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid ß-Protein-Induced Synapse Loss in Alzheimer's Disease.

Amyloid ß-protein (Aß) toxicity is hypothesized to play a seminal role in Alzheimer's disease (AD) pathogenesis. However, it remains unclear how Aß causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of Aß-induced synaptic injury is related to the cleavage of amyloid ß precursor protein (APP) at position D664 by caspases that release the putatively cytotoxic C31 peptide. In organotypic slice cultures derived from mice with a knock-in mutation in the APP gene (APP D664A) to inhibit caspase cleavage, Aß-induced synaptic injury is markedly reduced in two models of Aß toxicity. Loss of dendritic spines is also attenuated in mice treated with caspase inhibitors. Importantly, the time-dependent dendritic spine loss is correlated with localized activation of caspase-3 but is absent in APP D664A cultures. We propose that the APP cytosolic domain plays an essential role in Aß-induced synaptic damage in the injury pathway mediated by localized caspase activation.

Brain function early after stroke in relation to subsequent recovery.

This study aimed to characterize brain activation and perfusion early after stroke within cortical regions that would later change activation during recovery. Patients were studied serially after stroke (mean t1, = 16 days after stroke, t2 = 3.5 months later) using perfusion-weighted imaging and functional magnetic resonance imaging during finger movement. Controls (n = 7) showed no significant change in regional activation volumes over time. Among stroke patients (n = 8), however, recovery was accompanied by several patterns of functional magnetic resonance imaging change, with increased activation volumes over time in five patients and decreased in two. Most regions increasing activation over time were in the stroke hemisphere. Of the five patients showing increased activation over time, specific activation foci enlarged at t2 were already activated at t1 in four patients, and at least one focus growing from t1 to t2 was in a different arterial distribution from the infarct in all five patients. Perfusion of sensorimotor cortex at t1 was generally not reduced in the stroke hemisphere (94% of noninfarcted hemisphere). Improved clinical outcome was related to increased activation within sensory cortices of both brain sides, including bilateral secondary somatosensory areas. Early after stroke, cortical activation that will later increase in parallel with recovery is often already identifiable, can be remote from the vascular territory of the infarct, and is not likely hindered by reduced perfusion. The findings may be useful for restorative interventions introduced during the weeks after a stroke.

Morphology of superior colliculus- and middle temporal area-projecting neurons in primate primary visual cortex.

Layers 5 and 6 of primate primary visual cortex (V1) harbor morphologically diverse cell groups that have corticocortical and corticosubcortical projections. Layer 6 middle temporal area (MT)-projecting neurons are particularly interesting, as they are the only deep-layer cortical neurons that provide both corticocortical feedforward inputs (to area MT) and corticosubcortical feedback projections (to superior colliculus [SC]) (Fries et al. [1985] Exp Brain Res 58:613-616). However, due to limitations in anatomical tracing techniques, little is known about the detailed morphologies of these cells. We therefore applied a genetically modified rabies virus as a retrograde tracer to fill the dendrites of projection neurons with green fluorescent protein (GFP) (Wickersham et al. [2007] Nat Methods 4:47-49). We injected virus into SC or area MT of macaque monkeys and examined labeled cells in V1. Two-thirds of labeled neurons following SC injections were found in layer 5, consisting of "tall-tufted" and "nontufted" cells; the remaining cells were layer 6 "nontufted." Area MT injections labeled neurons in layers 4B and 6, as previously described (Shipp and Zeki [1989] Eur J Neurosci 1:309-332). The layer 6 neurons projecting to MT were remarkably similar to the layer 6 SC-projecting neurons. In contrast to the dense and focused dendritic arbors of layer 5 "tall-tufted" pyramids, all "nontufted" cells had sparse, but unusually long basal dendrites. The nontufted cells closely resemble Meynert cells (le Gros Clark [1942] J Anat 76:369-376; Winfield et al. [1983] Proc R Soc Lond B Biol Sci 217:129-139), but the full in vivo reconstructions presented here show that their basal dendrites can extend much further (up to 1.2 mm) and are less asymmetric than inferred from Golgi reconstructions.

Motor cortex activation is preserved in patients with chronic hemiplegic stroke.

Many central nervous system conditions that cause weakness, including many strokes, injure corticospinal tract but leave motor cortex intact. Little is known about the functional properties of surviving cortical regions in this setting, in part because many studies have used probes reliant on the corticospinal tract. We hypothesized that many features of motor cortex function would be preserved when assessed independent of the stroke-affected corticospinal tract. Functional MRI was used to study 11 patients with chronic hemiplegia after unilateral stroke that spared regions of motor cortex. Activation in stroke-affected hemisphere was evaluated using 3 probes independent of affected corticospinal tract: passive finger movement, a hand-related visuomotor stimulus, and tapping by the nonstroke index finger. The site and magnitude of cortical activation were similar when comparing the stroke hemisphere to findings in 19 control subjects. Patients activated each of 8 cortical regions with similar frequency as compared to controls, generally with a smaller activation volume. In some cases, clinical measures correlated with the size or the site of stroke hemisphere activation. The results suggest that, despite stroke producing contralateral hemiplegia, surviving regions of motor cortex actively participate in the same proprioceptive, visuomotor, and bilateral movement control processes seen in control subjects.