Down+Syndrome

= =

** __DOWN SYNDROME__ **

Down syndrome is a chromosomal disorder, commonly referred to as a trisomy of chromosome 21, in which extra genetic material ultimately causes over-expression of certain genes (**Figure 1**) (Korenberg et al., 1994). This abnormality manifests itself as symptoms of characteristic physical features, such as a flattened nose and face, upward-slanting eyes, epicanthic folds, stunted growth, and shortened extremities, amongst many other prominently atypical features (**Figure 1**) (Korenberg et al., 1990). Deterioration of cognitive function, in the form of mental retardation, is another common feature noted in Down syndrome patients. There seems to be some degree of comorbidity between Down syndrome and Alzheimer's disease, as indicated by the increasing prevalence of dementia as these patients age (Korenberg et al., 1994). This higher susceptibility to Alzheimer’s disease causes many alterations in typical mental processes with increasing age. Correspondingly, the characteristic decline in cognitive function seen in Down syndrome patients provides ample opportunities for research into cognitive-based interventions and therapies to improve the overall quality of life for patients and their surrounding loved ones.



flat

 =** 1.1 Cognitive Symptoms ** =

Patients diagnosed with Down syndrome exhibit a characteristic impairment of cognition, ranging from mild to moderate damage (Committee on Genetics, 2001). In addition to the presence of some extent of mental retardation, it is extremely common for these patients to show a delay in language abilities and in the development of fine and gross motor skills, which may further interfere with adequate mental development (**Figure 2**) (de Campos, Rocha, & Savelsbergh, 2010).

Along with the decline in cognitive function, the eventual onset of some form of dementia is rather common in the prognosis of Down syndrome. Evidence from MRI scans reveals a reduction in total brain mass, especially in the hippocampal and amygdala regions, as well as an increase in ventricular size (Pearlson et al., 1998). These neural alterations correlate with impairments in several domains of cognition, such as memory, thought processes, language, judgment decisions, and behaviour (McKhann, Drachman, Folstein, Katzman, Price, & Stadlan, 1984; Amieva et al., 2005; Graham, Emery, & Hodges, 2004; Lalonde, Fukuchi, & Strazielle, 2012).

=** 1.2 The Amyloid Beta Precursor Protein (APP) and Amyloid Beta ** =

APP is a membrane-spanning protein implicated in the monitoring and control of neuronal activity, and in memory and plasticity processes (Turner, O’Connor, Tate, & Abraham, 2003). This protein is widely recognized as the precursor molecule in the formation of the distinctive amyloid plaques found in the brains of Alzheimer’s disease patients, through a systematic proteolysis to generate an amyloid fibrillar form of amyloid beta (**Figure 3**) (Mattson, 2004). Via the action of β- and γ-secretases, APP undergoes a process of cleavage to generate several isoforms of the amyloid beta peptide, one of which is involved in conditions of disease (Hartmann, 1997).



The gene encoding for APP is located on chromosome 21 in humans, and mutations within crucial regions contribute to hereditary susceptibility to Alzheimer’s disease (**Figure 4**). These mutations may result either in an increased amount of the amyloid beta peptide or in the production of a slightly longer and stickier form of the peptide. These alterations lead to the accumulation of clumps referred to as amyloid plaques, eventually leading to neuronal death and the gradual signs and symptoms of Alzheimer’s disease (Murrel, Farlow, Ghetti, & Benson, 1991).



=** 1.3 Alzheimer’s Disease ** =  Alzheimer’s disease is a neurological condition, characteristically involving progressive dementia. The basis of the pathology of this disease includes neuronal degeneration, the formation of amyloid plaques, and the presence of neurofibrillary tangles (**Figure 5**) (McKhann et al., 1984).

The following is a brief listing of some features arising with the clinical diagnosis of Alzheimer’s disease in affected patients:
 * dementia
 * cognitive deficits (e.g. aphasia, apraxia, agnosia)
 * <span style="font-family: Georgia,serif; font-size: 16px;">gradual impairment of memory, including plateaus in the course of deterioration
 * <span style="font-family: Georgia,serif; font-size: 16px;">intact consciousness and normal, age-appropriate computed tomography (CT) scans
 * <span style="font-family: Georgia,serif; font-size: 16px;">onset between the ages of 40 and 90, though more often after the age of 65
 * <span style="font-family: Georgia,serif; font-size: 16px;">associated symptoms of depression, insomnia, incontinence, hallucinations, delusions, illusions, catastrophic outbursts (i.e. verbal, emotional, physical), sexual disorders, weight loss, etc.
 * <span style="font-family: Georgia,serif; font-size: 16px;">eventual onset of seizures in advanced stages of the disease, similar to manifestations of @epilepsy (McKhann et al., 1984)

<span style="font-family: Georgia,serif; font-size: 16px;">Research on Alzheimer’s disease based on longitudinal studies may offer further knowledge on the natural history of the disease to allow for simple subtyping, which has potential purposes to assess the efficacy of therapeutic interventions. **Table 1** lists some laboratory assessments and the resulting data observed using each technique in Alzheimer’s disease patients (McKhann et al., 1984):

<span style="font-family: Georgia,serif; font-size: 16px;">increased width of the third ventricle <span style="font-family: Georgia,serif; font-size: 16px;">narrowed gyri <span style="font-family: Georgia,serif; font-size: 16px;">widened sulci ||
 * **<span style="font-family: Georgia,serif; font-size: 16px;">Table 1 **
 * <span style="font-family: Georgia,serif;">// Characteristic Features Observed in Alzheimer’s Disease Patients with Laboratory Techniques // ** ||
 * <span style="display: block; font-family: Georgia,serif; font-size: 16px; text-align: center;">Laboratory Assessment Method || <span style="display: block; font-family: Georgia,serif; font-size: 16px; text-align: center;">Observation in Alzheimer’s Disease Patients ||
 * <span style="font-family: Georgia,serif; font-size: 16px;">Electroencephalography (EEG) || <span style="font-family: Georgia,serif; font-size: 16px;">increased slow-wave activity ||
 * <span style="font-family: Georgia,serif; font-size: 16px;">Evoked potentials (EPs) || <span style="font-family: Georgia,serif; font-size: 16px;">increased latency of P300 potentials ||
 * <span style="font-family: Georgia,serif; font-size: 16px;">Computerized tomography (CT) || <span style="font-family: Georgia,serif; font-size: 16px;">increased volume of the ventricular system
 * <span style="font-family: Georgia,serif; font-size: 16px;">Regional cerebral blood flow (rCBF) || <span style="font-family: Georgia,serif; font-size: 16px;">decreased rCBF and cerebral metabolic rate ||
 * <span style="font-family: Georgia,serif; font-size: 16px;">Positron emission tomography (PET) || <span style="font-family: Georgia,serif; font-size: 16px;">cerebral hypometabolism ||

<span style="font-family: Georgia,serif; font-size: 16px;">Medical professionals, on the other hand, conduct various neuropsychological assessments for clinical validation of Alzheimer’s disease. **Table 2** lists some of these tests and the corresponding cognitive function the test measures (McKhann et al., 1984):

<span style="font-family: Georgia,serif; font-size: 16px;">recognition span test <span style="font-family: Georgia,serif; font-size: 16px;">Brown-Peterson Distractor test || <span style="font-family: Georgia,serif; font-size: 16px;">memory || <span style="font-family: Georgia,serif; font-size: 16px;">Boston Diagnostic Aphasia Examination <span style="font-family: Georgia,serif; font-size: 16px;">Western Aphasia test <span style="font-family: Georgia,serif; font-size: 16px;">Token test <span style="font-family: Georgia,serif; font-size: 16px;">Reporter’s test || <span style="font-family: Georgia,serif; font-size: 16px;">language skills || <span style="font-family: Georgia,serif; font-size: 16px;">Wechsler Adult Intelligence Scale subtest || <span style="font-family: Georgia,serif; font-size: 16px;">praxis || <span style="font-family: Georgia,serif; font-size: 16px;">Continuous-Performance test || <span style="font-family: Georgia,serif; font-size: 16px;">attention || <span style="font-family: Georgia,serif; font-size: 16px;">Hooper test || <span style="font-family: Georgia,serif; font-size: 16px;">visual perception || <span style="font-family: Georgia,serif; font-size: 16px;">The Poisoned Food Problem Task of Arenberg || <span style="font-family: Georgia,serif; font-size: 16px;">problem-solving skills || media type="youtube" key="7-P9lbTJ9Hw" height="315" width="420" align="center"
 * **<span style="font-family: Georgia,serif; font-size: 16px;">Table 2 **
 * <span style="font-family: Georgia,serif;">// Measures of Cognitive Function in Alzheimer’s Disease Patients with Neuropsychological Tests // ** ||
 * <span style="display: block; font-family: Georgia,serif; font-size: 16px; text-align: center;">Neuropsychological Assessment Method || <span style="display: block; font-family: Georgia,serif; font-size: 16px; text-align: center;">Cognitive Function Measured ||
 * <span style="font-family: Georgia,serif; font-size: 16px;">Mini-Mental State Examination || <span style="font-family: Georgia,serif; font-size: 16px;">orientation to place and time ||
 * <span style="font-family: Georgia,serif; font-size: 16px;">free-recall test
 * <span style="font-family: Georgia,serif; font-size: 16px;">Boston Naming test
 * <span style="font-family: Georgia,serif; font-size: 16px;">picture-copying test
 * <span style="font-family: Georgia,serif; font-size: 16px;">reaction-time task
 * <span style="font-family: Georgia,serif; font-size: 16px;">Gollin Incomplete-Pictures test
 * <span style="font-family: Georgia,serif; font-size: 16px;">Wisconsin Card-Sorting test

=<span style="font-family: Georgia,serif;">** 1.4 Natural Amyloid Beta and APP Gene Dosage ** = <span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px; height: 542px; width: 441px;"> <span style="font-family: Georgia,serif; font-size: 16px;">A general characteristic feature prevalent in all cases of Alzheimer’s disease is the abnormal and excessive accumulation of amyloid beta peptides, which lead to the formation of insoluble aggregates known as amyloid plaques (**Figure 6**). This progressive clustering is the result of aberrant processing of APP, the gene for which is located on chromosome 21 in humans (Selkoe, 1994). Individuals with Down syndrome contain an extra copy of chromosome 21, and thus, exhibit an increased APP gene dosage, resulting in the overexpression of APP. Consequently, these individuals almost certainly develop amyloid plaques after the age of 30, which lends itself to the comorbidity between Down syndrome and Alzheimer’s disease (Teller et al., 1996).

<span style="font-family: Georgia,serif; font-size: 16px;">Through postmortem imaging of the cerebral cortices from both healthy individuals and those affected with Down syndrome, it has been demonstrated that amyloid beta peptides are found in the brains of patients with Down syndrome, regardless of the absence or presence of amyloid plaques, but is not detected in the brains of healthy individuals. In the brains of individuals with Down syndrome, the total concentration of these amyloid beta peptides increases exponentially with age when amyloid plaques are present, in contrast to when the brains are free of plaques. Furthermore, when extended to fetal brains of Down syndrome cases, the presence of amyloid beta peptides is detected, suggesting that the onset of the preexisting metabolic conditions that lead to the eventual formation of plaques is present even at early stages of development (Teller et al., 1996).

<span style="font-family: Georgia,serif; font-size: 16px;">Relevant analyses have shown that amyloid beta peptides are present in the brains of Down syndrome patients much earlier than the manifestation of amyloid plaques. As well, these peptides are undetectable in age-matched healthy individuals and in individuals clinically diagnosed with conditions other than Down syndrome and Alzheimer’s disease. These findings indicate the role of amyloid beta in the progressive development of amyloid plaques (Teller et al., 1996).

<span style="font-family: Georgia,serif; font-size: 16px;">Several implications can be drawn from the given data. Possible mechanisms that eliminate the presence of amyloid beta in healthy brains are not functional in the brains of Down syndrome patients, plausibly due to the overloaded amount of amyloid beta from the overexpression of APP (Rumble et al., 1989). Nonetheless, it is noteworthy that the appearance of accumulated amyloid plaques in Down syndrome patients is detected after a delay of approximately 20 years, in spite of the consistent detection of the amyloid beta peptides (Teller et al., 1996). These peptides are highly aggregable; hence, some alternative mechanism in the brains of individuals with Down syndrome must prevent the formation of amyloid plaques for a long duration (Hilbich, Kisters-Woike, Reed, Masters, & Beyreuther, 1991). If this is certainly the case, advanced approaches to diagnostic detection and disease prevention may come into effect with further research on neural concentrations of amyloid beta peptides and APP gene dosages.

=<span style="font-family: Georgia,serif;">** 1.5 Levels of Amyloid Beta ** = <span style="font-family: Georgia,serif; font-size: 16px;">Levels of the amyloid beta peptide are chronically elevated in individuals with Down syndrome, and this correlates with the progressive onset of Alzheimer’s disease within these patients, due to the formation of amyloid plaques and the degeneration of cholinergic neurons within the basal forebrain (Hyman, 1992). Studies have been conducted to examine whether the upsurge in neural levels of amyloid beta in Down syndrome children play a role in intellectual disability (Netzer et al., 2010). Among the studies conducted, Netzer et al. (2010) were a group of researchers to use model mice to observe the effects of lowering the abundant levels of amyloid beta using a γ-secretase inhibitor (**Figure 7**).

<span style="font-family: Georgia,serif; font-size: 16px;">These mice, referred to as Ts65Dn mice, are widely recognized as models of non-human cases of Down syndrome (Davisson et al., 1993). These mice characteristically contain three partial copies of mouse chromosome 16, which includes genes that are homologous to the ones found in human chromosome 21 (Akeson, Lambert, Narayanswami, Gardiner, Bechtel, & Davisson, 2001). Among these genes, the APP gene is also triplicated, and these mice invariably show signs of gradual cognitive deficits, among other attributes that are common to adult Down syndrome and Alzheimer’s disease patients (Godridge, Reynolds, Czudek, Calcutt, & Benton, 1987).

<span style="font-family: Georgia,serif; font-size: 16px;">After administering the protease inhibitor to decrease the levels of amyloid beta, performance on the Morris water maze noticeably improved, as the deficits in spatial learning and memory were effectively rescued (**Figure 8**). These obtained results provide support for the claim that cognitive function exhibits a profound response to variability in the neural levels of the amyloid beta peptide in animals that display cognitive impairments, such as those diagnosed with Alzheimer’s disease or Down syndrome (Netzer et al., 2010).



=<span style="font-family: Georgia,serif;">** 1.6 Cognitive-Based Interventions ** = =<span style="font-family: Georgia,serif; font-size: 16px;">media type="youtube" key="7uUNKRaWsN4" height="315" width="420" align="right" =

<span style="font-family: Georgia,serif; font-size: 16px;">The comorbidity between Down syndrome and Alzheimer’s disease is becoming an increasingly prominent focus in clinical research. The onset of Alzheimer’s disease in the prognosis of Down syndrome occurs approximately at the age of 60: at this time, family and loved ones, due to the process of aging, are least able to provide adequate care, leading to a greater burden on caregivers (Strydom et al., 2010; Courtenay, Jokinen, & Strydom, 2010).

<span style="font-family: Georgia,serif; font-size: 16px;">Emerging evidence on the associations between distinct pathologies of Alzheimer’s disease may offer significant indications towards the causal mechanisms of this disease and, thus, contribute to the development of novel therapies, preventive medicine, and early detection of the disease in Down syndrome patients (Takata & Kitamura, 2012). Nonetheless, clinicians are still in need of a far greater understanding of the neurobiological basis of Down syndrome to be able to design and administer effective treatment methods.

<span style="font-family: Georgia,serif; font-size: 16px;">And at last, a conclusive video clip presenting a brief overview of Down syndrome:

media type="youtube" key="hLsjfoT_sSw" height="315" width="420" align="center"

=<span style="font-family: Georgia,serif;">**__See also__** =
 * <span style="font-family: Georgia,serif; font-size: 16px;">@neurogenetic diseases
 * <span style="font-family: Georgia,serif; font-size: 16px;">Creutzfeldt-Jakob disease (CJD)
 * <span style="font-family: Georgia,serif; font-size: 16px;">@Wilson’s disease
 * <span style="font-family: Georgia,serif; font-size: 16px;">@Niemann-Pick disease
 * <span style="font-family: Georgia,serif; font-size: 16px;">@Turner syndrome
 * <span style="font-family: Georgia,serif; font-size: 16px;">music therapy for Alzheimer’s disease
 * <span style="font-family: Georgia,serif; font-size: 16px;">nerve regeneration in the peripheral nervous system, as a form of treatment for Alzheimer’s disease
 * <span style="font-family: Georgia,serif; font-size: 16px;">cognitive dysfunction treatment for Alzheimer’s disease

=<span style="font-family: Georgia,serif;">__** References **__ = <span style="font-family: Georgia,serif; font-size: 16px;">Akeson, E. C., Lambert, J. P., Narayanswami, S., Gardiner, K., Bechtel, L. J., & Davisson, M. T. (2001). Ts65Dn – localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome. //Cytogenet Cell Genet, 93//, 270-276.

<span style="font-family: Georgia,serif; font-size: 16px;">Alzheimer’s disease. (n. d.). //Jefferson Hospital for Neuroscience//. Retrieved from: []

<span style="font-family: Georgia,serif; font-size: 16px;">Alzheimer’s disease mechanisms and processes. (n. d.). //National Institute on Aging//. Retrieved from: []

<span style="font-family: Georgia,serif; font-size: 16px;">Amieva, H., Jacqmin-Gadda, H., Orgogozo, J. M., Le Carret, N., Helmer, C., Letenneur, L., … & Dartigues, J. F. (2005). The 9 year cognitive decline before dementia of the Alzheimer type: A prospective population-based study. //Brain, 128//(5), 1093–1111.

<span style="font-family: Georgia,serif; font-size: 16px;">Committee on Genetics. (2001). Health supervision for children with Down syndrome. //Pediatrics, 107//(2), 442-449.

<span style="font-family: Georgia,serif; font-size: 16px;">Courtenay, K., Jokinen, N. S., & Strydom, A. (2010). Caregiving and adults with intellectual disabilities affected by dementia. //JPPID, 7//(1), 26-33.

<span style="font-family: Georgia,serif; font-size: 16px;">Davisson, M. T., Schmidt, C., Reeves, R. H., Irving, N. G., Akeson, E. C., Harris, B. S., & Bronson, R. T. (1993). Segmental trisomy as a mouse model for Down syndrome. //Prog Clin Biol Res, 384//, 117-133.

<span style="font-family: Georgia,serif; font-size: 16px;">de Campos, A. C., Rocha, N. A. C. F., & Savelsbergh, G. J. P. (2010). Development of reaching and grasping skills in infants with Down syndrome. //Res Dev Disabil, 31//(1), 70-80.

<span style="font-family: Georgia,serif; font-size: 16px;">Down’s syndrome karyotype. (n. d.). //Science Photo Library//. Retrieved from: []

<span style="font-family: Georgia,serif; font-size: 16px;">Genomic views for APP gene. (n. d.). //Weizmann Institute of Science//. Retrieved from: []

<span style="font-family: Georgia,serif; font-size: 16px;">Godridge, H., Reynolds, G. P., Czudek, C., Calcutt, N. A., & Benton, M. (1987). Alzheimer-like neurotransmitter deficits in adult Down’s syndrome brain tissue. //J Neurol Neurosurg Psychiatry 50//, 775–778.

<span style="font-family: Georgia,serif; font-size: 16px;">Graham, N. L., Emery, T., & Hodges, J. R. (2004). Distinctive cognitive profiles in Alzheimer’s disease and subcortical vascular dementia. //J Neurol Neurosurg Psychiatry, 75//, 61-71.

<span style="font-family: Georgia,serif; font-size: 16px;">Hartmann, T., Bieger, S. C., Brühl, B., Tienari, P. J., Ida, N., Allsop, D., … & Beyrouther, K. (1997). Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides. //Nat Med, 3//, 1016-1020.

<span style="font-family: Georgia,serif; font-size: 16px;">Hilbich, C., Kisters-Woike, B., Reed, J., Masters, C. L., & Beyreuther, K. (1991). Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer’s disease. //J Mol Biol, 218//(1), 149-163.

<span style="font-family: Georgia,serif; font-size: 16px;">Hyman, B. T. (1992). Down syndrome and Alzheimer disease. //Prog Clin Biol Res, 379//, 123-142.

<span style="font-family: Georgia,serif; font-size: 16px;">Korenberg, J. R., Chen, X. N., Schipper, R., Sun, Z., Gonsky, R., Gerwehr, S., … & Disteche, C. (1994). Down syndrome phenotypes: The consequences of chromosomal imbalance. //Proc Natl Acad Sci U S A, 91//(11), 4997-5001.

<span style="font-family: Georgia,serif; font-size: 16px;">Korenberg, J. R., Kawashima, H., Pulst, S-M., Ikeuchi, T., Ogasawara, N., Yamamoto, K., … & Epstein, C. J. (1990). Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. //Am J Hum Genet, 47//(2), 236-246.

<span style="font-family: Georgia,serif; font-size: 16px;">Lalonde, R., Fukuchi, K., & Strazielle, C. (2012). APP transgenic mice for modelling behavioural and psychological symptoms of dementia (BPSD). //Neurosci Biobehav Rev, 36//(5), 1357-1375.

<span style="font-family: Georgia,serif; font-size: 16px;">Mattson, M. P. (2004). Pathways towards and away from Alzheimer’s disease. //Nature, 430//(7000), 631-639.

<span style="font-family: Georgia,serif; font-size: 16px;">McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984). Clinical diagnosis of Alzheimer’s disease. //Neurology, 34//(7), 939-944.

<span style="font-family: Georgia,serif; font-size: 16px;">Murrel, J., Farlow, M., Ghetti, B., & Benson, M. D. (1991). A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. //Science, 254//(5028), 97-99.

<span style="font-family: Georgia,serif; font-size: 16px;">Netzer, W. J., Powell, C., Nong, Y., Blundell, J., Wong, L., Duff, K., … & Greengard, P. (2010). Lowering β-amyloid levels rescues learning and memory in a Down syndrome mouse model. //PLoS ONE, 5//(6), 1-5.

<span style="font-family: Georgia,serif; font-size: 16px;">New drug could help Alzheimer’s patients. (2011). //National Institution on Aging//. Retrieved from: []

<span style="font-family: Georgia,serif; font-size: 16px;">P7C3 prevents cognitive decline in aging. (n. d.). //2M BioTech//. Retrieved from: []

<span style="font-family: Georgia,serif; font-size: 16px;">Pearlson, G. D., Breiter, S. N., Aylward, E. H., Warren, A. C., Grygorcewicz, M., Frangou, S., … & Pulsifer, M. B. (1998). MRI brain changes in subjects with Down syndrome with and without dementia. //Dev Med Child Neurol, 40//(5), 326-334.

<span style="font-family: Georgia,serif; font-size: 16px;">Rumble, B., Retallack, R., Hilbich, C., Simms, G., Multhaup, G., Martins, R., … & Masters, C. L. (1989). Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. //N Engl J Med, 320//, 1446-1452.

<span style="font-family: Georgia,serif; font-size: 16px;">Schenk et al. (1999). Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. //Great C0ntroversies in Neurobiology, Brown University//. Retrieved from: [].

<span style="font-family: Georgia,serif; font-size: 16px;">Selkoe, D. J. (1994). Cell biology of the amyloid β-protein precursor and the mechanism of Alzheimer’s disease. //Annu Rev Cell Biol, 10//, 373-403.

<span style="font-family: Georgia,serif; font-size: 16px;">Smida, V. (2011). Down syndrome – Trisomy 21 or Mongolism. //Genetic Disorders, Pediatrics, Doctor Tipster//. Retrieved from: []

<span style="font-family: Georgia,serif; font-size: 16px;">Strydom, A., Shooshtari, S., Lee, L., Raykar, V., Torr, J., Tsiouris, J., … & Maaskant, M. (2010). Dementia in older adults with intellectual disabilities – epidemiology, presentation, and diagnosis. //JPPID, 7//(2), 96-110.

<span style="font-family: Georgia,serif; font-size: 16px;">Takata, K. & Kitamura, Y. (2012). Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer’s disease; Tangle formation, amyloid-β, and microglia in Alzheimer’s disease. //J Pharmacol Sci, 118//(3), 331-337.

<span style="font-family: Georgia,serif; font-size: 16px;">Teller, J. K., Russo, C., DeBusk, L. M., Angelini, G., Zaccheo, D., Dagna-Bricarelli, F., … & Gambetti, P. (1996). Presence of soluble amyloid β-peptide precedes amyloid plaque formation in Down’s syndrome. //Nat Med, 2//(1), 93-95.

<span style="font-family: Georgia,serif; font-size: 16px;">The gregarious gene. (2009). //Salk Institute for Biological Studies//. Retrieved from: []

<span style="font-family: Georgia,serif; font-size: 16px;">Turner, P. R., O’Connor, K., Tate, W. P., & Abraham, W. C. (2003). Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. //Prog Neurobiol, 70//(1), 1-32.

<span style="font-family: Georgia,serif; font-size: 16px;"> include component="comments" page="Down Syndrome" limit="10"