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Mice that overexpress the human mutant amyloid precursor protein (hAPP) show learning deficits, but the apparent lack of a relationship between these deficits and the progressive beta-amyloid plaque formation that the hAPP mice display is puzzling. In the water maze, hAPP mice are impaired before and after amyloid plaque deposition. Here we show, using a new water-maze training protocol, that PDAPP mice also exhibit a separate age-related deficit in learning a series of spatial locations. This impairment correlates with beta-amyloid plaque burden and is shown in both cross-sectional and longitudinal experimental designs. Cued navigation and object-recognition memory are normal. These findings indicate that A beta overexpression and/or A beta plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimer's-disease-type pathologies.

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.

SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.

The aspartyl protease ␤-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates processing of amyloid precursor protein (APP) into amyloid ␤ (A␤) peptide, the major component of Alzheimer disease (AD) plaques. To determine the role that BACE1 plays in the development of A␤-driven AD-like pathology, we have crossed PDAPP mice, a transgenic mouse model of AD overexpressing human mutated APP, onto mice with either a homozygous or heterozygous BACE1 gene knockout. Analysis of PDAPP/BACE(؊/؊) mice demonstrated that BACE1 is absolutely required for both A␤ generation and the development of age-associated plaque pathology. Furthermore, synaptic deficits, a neurodegenerative pathology characteristic of AD, were also reversed in the bigenic mice. To determine the extent of BACE1 reduction required to significantly inhibit pathology, PDAPP mice having a heterozygous BACE1 gene knock-out were evaluated for A␤ generation and for the development of pathology. Although the 50% reduction in BACE1 enzyme levels caused only a 12% decrease in A␤ levels in young mice, it nonetheless resulted in a dramatic reduction in A␤ plaques, neuritic burden, and synaptic deficits in older mice. Quantitative analyses indicate that brain A␤ levels in young APP transgenic mice are not the sole determinant for the changes in plaque pathology mediated by reduced BACE1. These observations demonstrate that partial reductions of BACE1 enzyme activity and concomitant A␤ levels lead to dramatic inhibition of A␤-driven AD-like pathology, making BACE1 an excellent target for therapeutic intervention in AD.Alzheimer disease is the major cause of dementia in elderly people and is characterized by progressive cognitive decline. There is no cure, current treatments offer only temporary relief, and death invariably ensues. Substantial evidence suggests that the amyloid ␤ peptide (A␤) 6 is the cause of Alzheimer disease (AD)-associated neuropathology (1). A␤ is derived by sequential proteolysis of the amyloid precursor protein (APP) through ␤-and ␥-secretase activities and is widely deposited in amyloid plaques in the brains of individuals with AD (2, 3). Therefore, inhibiting the action of one or both of these enzymatic activities may provide inaugural disease-modifying therapies for AD.The aspartyl protease BACE1 is the primary ␤-secretase (4 -6) and is the sole ␤-secretase in mice, since its genetic ablation fully abolishes A␤ generation (7-9). Early reports indicated that BACE1 knock-out animals are healthy and fertile, with no histological pathologies, suggesting that inhibition of BACE1 for therapeutic intervention in AD would have no mechanism related toxicities (7, 9, 10). In contrast, recent reports of partially penetrant lethality and cognitive deficits in BACE1 knock-out animals do suggest potential liabilities of complete BACE1 inhibition (11, 12). As the initiating enzyme in the generation of A␤, BACE1 is a key drug target and would be predicted to abrogate pathologies associated with any form of A␤. To avoid potential side effects re...

The performance of amnesic patients was assessed on five tasks, which have figured prominently in the development of animal models of human amnesia in the monkey. The amnesic patients were impaired on four of these tasks (delayed nonmatchingto sample, object-reward association, 8-pair concurrent discrimination learning, and an object discrimination task), in correspondence with previous findings for monkeys with bilateral medial temporal or diencephalic lesions. Moreover, performance of the amnesic patients correlated with the ability to verbalize the principle underlying the tasks and with the ability to describe and recognize the stimulus materials. These tasks therefore seem to be sensitive to the memory functions that are affected in human amnesia, and they can provide valid measures of memory impairment in studies with monkeys. For the fifth task (24-hour concurrent discrimination learning), the findings for the amnesic patients did not correspond to previous findings for operated monkeys. Whereas monkeys with medial temporal lesions reportedly learn this task at a normal rate, the amnesic patients were markedly impaired. Monkeys may learn this task differently than humans. Damage to the medial temporal region or the midline diencephalic region of the human brain causes amnesia in the absence of other intellectual impairment (

BackgroundThe universal presence of a gene (SMN2) nearly identical to the mutated SMN1 gene responsible for Spinal Muscular Atrophy (SMA) has proved an enticing incentive to therapeutics development. Early disappointments from putative SMN-enhancing agent clinical trials have increased interest in improving the assessment of SMN expression in blood as an early “biomarker” of treatment effect.MethodsA cross-sectional, single visit, multi-center design assessed SMN transcript and protein in 108 SMA and 22 age and gender-matched healthy control subjects, while motor function was assessed by the Modified Hammersmith Functional Motor Scale (MHFMS). Enrollment selectively targeted a broad range of SMA subjects that would permit maximum power to distinguish the relative influence of SMN2 copy number, SMA type, present motor function, and age.ResultsSMN2 copy number and levels of full-length SMN2 transcripts correlated with SMA type, and like SMN protein levels, were lower in SMA subjects compared to controls. No measure of SMN expression correlated strongly with MHFMS. A key finding is that SMN2 copy number, levels of transcript and protein showed no correlation with each other.ConclusionThis is a prospective study that uses the most advanced techniques of SMN transcript and protein measurement in a large selectively-recruited cohort of individuals with SMA. There is a relationship between measures of SMN expression in blood and SMA type, but not a strong correlation to motor function as measured by the MHFMS. Low SMN transcript and protein levels in the SMA subjects relative to controls suggest that these measures of SMN in accessible tissues may be amenable to an “early look” for target engagement in clinical trials of putative SMN-enhancing agents. Full length SMN transcript abundance may provide insight into the molecular mechanism of phenotypic variation as a function of SMN2 copy number.Trial Registry Clinicaltrials.gov NCT00756821

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